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Liu X, Wang M, Xu B, Ma X, Jiang Y, Huang H, Shi Z, Wu H, Wu Z, Guo S, Zhao J, Zhao J, Li X, Liang L, Guo Z, Shi L, Sun C, Wang N. Discovery and identification of semaphorin 4D as a bioindicator of high fracture incidence in type 2 diabetic mice with glucose control. J Adv Res 2025:S2090-1232(25)00174-2. [PMID: 40073972 DOI: 10.1016/j.jare.2025.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 03/06/2025] [Accepted: 03/07/2025] [Indexed: 03/14/2025] Open
Abstract
INTRODUCTION Bone fracture is increasing in patients with type 2 diabetes mellitus (T2DM) due to skeletal fragility. Most antidiabetics are expected to reduce the incidence of fracture in patients with T2DM, however the results are disappointing. Metformin and GLP-1 receptor agonists have a neutral or minor positive effect in reducing fractures. OBJECTIVES We aim to reveal the mechanism of fracture in patients with T2DM treated with metformin or exendin-4, explore the key regulators responsible for bone fragility in T2DM. METHODS Trabecular and cortical masses in mice with T2DM were analyzed using micro-computed tomography. Biomechanical strength of bone was determined according to three-point bending, and the expression of bone-associated factors was examined with enzyme-linked immunosorbent assays. Important proteins and miRNAs were identified using proteomics analysis and deep screening analysis. Lastly, immunoprecipitation-mass spectrometry and dual-luciferase reporter analysis were used to identify key molecular signals. RESULTS We found that sermaphorin 4D (Sema4D) is the key regulator of bone fragility in T2DM. Exendin-4 increased the biomechanical properties of bone by decreasing serum Sema4D levels, and metformin has little effect on Sema4D. Anti-sema4D treatment could improve bone strength in T2DM mice compared with metformin or exendin-4. The biomechanical properties of bone were comparable between anti-Sema 4D and the combination of metformin and exendin-4. Exendin-4 promoted osteogenesis of BMSCs by activating CRMP2 to reverse the effect of sema4D. Metformin increased miR-140-3p levels, which decreased plexin B1 expression in bone mesenchymal stem cells. Metformin increased the effect of exendin-4 with more GLP-1 receptor expression to increase the biomechanical strength of bone via miR-140-3p-STAT3-miR-3657 signaling. CONCLUSION Blood glucose level is not the major factor contributing to impairment in bone remodeling. Sema4D is responsible for the increase in the incidence of bone fractures in T2DM. Accordingly, we proposed an effective therapeutic strategy to eliminate the effect of sema4D.
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Affiliation(s)
- Xuanchen Liu
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100 Shaanxi, China; Department of Nutrition, Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China
| | - Mo Wang
- Department of Orthopaedics, Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China
| | - Bin Xu
- Department of Orthopaedics, Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China
| | - Xue Ma
- Department of Pharmacology, School of Pharmacy, Air Force Military Medical University, Xi'an 710032 Shaanxi, China
| | - Yangzi Jiang
- School of Biomedical Sciences, Faculty of Medicine, Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region; Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Special Administrative Region of China, Hong Kong Special Administrative Region
| | - Hai Huang
- Department of Orthopaedics, Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China
| | - Zengzeng Shi
- Department of Gynecology and Obstetrics, Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China
| | - Hao Wu
- Department of Orthopaedics, Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China
| | - Zhigang Wu
- Department of Orthopaedics, Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China
| | - Shuo Guo
- Department of Orthopaedics, Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China
| | - Jungang Zhao
- Department of Orthopaedics, Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China
| | - Jian Zhao
- Department of Orthopaedics, Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China
| | - Xiaokang Li
- Department of Orthopaedics, Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China
| | - Li Liang
- Department of Orthopaedics, Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China
| | - Zheng Guo
- Department of Orthopaedics, Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China
| | - Lei Shi
- Department of Orthopaedics, First Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China.
| | - Chao Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100 Shaanxi, China.
| | - Ning Wang
- Department of Orthopaedics, Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038 Shaanxi, China.
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Tian Y, Liu H, Bao X, Li Y. Semaglutide promotes the proliferation and osteogenic differentiation of bone-derived mesenchymal stem cells through activation of the Wnt/LRP5/β-catenin signaling pathway. Front Pharmacol 2025; 16:1539411. [PMID: 40129942 PMCID: PMC11931165 DOI: 10.3389/fphar.2025.1539411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 02/17/2025] [Indexed: 03/26/2025] Open
Abstract
Diabetes mellitus is a global disease in which alterations in the internal environment disrupt the bone-fat balance, contributing to osteoporosis. Semaglutide, a single-target, long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), has been shown to promote osteogenesis in vitro, but the underlying mechanism remains unclear. In this study, the ability of Semaglutide to promote the proliferation of bone-derived mesenchymal stem cells (BMSCs) was determined by CCK-8 kit and flow cytometry, Alkaline phosphatase (ALP) staining and alizarin red S staining showed that semaglutide increased ALP activity and the proportion of mineralised nodules during induction of osteogenesis, wound healing assay to evaluate the pro-migratory ability of semaglutide on BMSCs.Western blotting and RT-PCR showed that semaglutide promoted the mRNA and protein expression of osteocalcin (OCN) and Runt-related transcription factor 2 (RUNX2), and further determined the OCN expression level by immunofluorescence. RNA sequencing was performed to analyze the mechanisms underlying BMSC osteogenesis after semaglutide intervention. Enrichment of RNA sequencing data indicated that the Wnt/LRP5/β-catenin pathway was activated after treatment with semaglutide. Western blotting further confirmed the upregulation of Wnt pathway-associated protein levels by semaglutide. Dickkopf-1 (DKK1) and LiCl (lithium chloride) are common inhibitors and agonists of the Wnt/β-catenin pathway. The addition of semaglutide resulted in the partial reversal of the inhibitory effect of DKK1 on osteogenic differentiation, with the administration of LiCl and semaglutide further accelerating the osteogenic process. In addition to alterations in gene and protein expression levels, these changes are also reflected in alkaline phosphatase (ALP) activity and calcium deposition. Therefore, we suggest that semaglutide can promote the proliferation and osteogenic differentiation of BMSCs in vitro via the Wnt/LRP5/β-catenin signalling pathway.
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Affiliation(s)
- Yawei Tian
- Department of Endocrinology, Hebei Medical University Third Hospital, Shijiazhuang, China
| | - Huiming Liu
- Department of Stomatology, Hebei Medical University Second Hospital, Shijiazhuang, China
| | - Xiaoxue Bao
- Department of Endocrinology, Hebei Medical University Third Hospital, Shijiazhuang, China
| | - Yukun Li
- Department of Endocrinology, Hebei Medical University Third Hospital, Shijiazhuang, China
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Bao X, Liu C, Liu H, Wang Y, Xue P, Li Y. Association between polymorphisms of glucagon-like peptide-1 receptor gene and susceptibility to osteoporosis in Chinese postmenopausal women. J Orthop Surg Res 2024; 19:869. [PMID: 39716293 DOI: 10.1186/s13018-024-05361-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 12/11/2024] [Indexed: 12/25/2024] Open
Abstract
BACKGROUND The influence of the glucagon-like peptide-1 receptor (GLP-1R) on bone metabolism is well-established. However, it has been observed that single nucleotide polymorphisms (SNPs) in the GLP-1R gene can partially affect its function. Therefore, this study aims to investigate the association between SNPs in the GLP-1R gene and postmenopausal osteoporosis (PMOP) within the Chinese Han population. METHODS This study employed a cross-sectional case-control design, recruiting a total of 152 participants, including 76 patients with osteoporosis (OP) (case group) and 76 healthy individuals (control group). Seven tag SNPs of GLP-1R were selected from the National Center of Biotechnology Information and Genome Variation Server. The association between GLP-1R polymorphisms and PMOP risk was assessed using different genetic models and haplotypes, while also exploring SNP-SNP and SNP-environment interactions. RESULTS Our results showed that minor alleles A at rs3765468, A at rs3765467 and G at rs4714210 showed significant associations with an increased risk of OP. Individuals with rs3765468 AG-AA genotype and rs3765467 AG-AA genotype exhibited a significantly higher risk of PMOP. Moreover, haplotype analysis revealed a significant association of the GACACA haplotype on PMOP risk (P = 0.033). Additionally, a multiplicative interaction was observed between rs3765468 and rs3765467 that was associated with an increased risk of PMOP (Pinteraction = 0.012). CONCLUSIONS Specific SNPs in the GLP-1R gene were linked to an increased risk of PMOP. This study improves our understanding of the genetic basis of PMOP in this population and suggests that genetic screening can identify individuals at risk for developing PMOP, enabling early prevention.
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Affiliation(s)
- Xiaoxue Bao
- Department of Endocrinology, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
- Key Orthopaedic Biomechanics Laboratory of Hebei Province, Orthopedic Research Institution of Hebei Province, Shijiazhuang, Hebei, China
| | - Chang Liu
- Department of Endocrinology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Huiming Liu
- Department of Endocrinology, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
- Department of Prosthodontics, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yan Wang
- Department of Endocrinology, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
- Key Orthopaedic Biomechanics Laboratory of Hebei Province, Orthopedic Research Institution of Hebei Province, Shijiazhuang, Hebei, China
| | - Peng Xue
- Department of Endocrinology, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
- Key Orthopaedic Biomechanics Laboratory of Hebei Province, Orthopedic Research Institution of Hebei Province, Shijiazhuang, Hebei, China
| | - Yukun Li
- Department of Endocrinology, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China.
- Key Orthopaedic Biomechanics Laboratory of Hebei Province, Orthopedic Research Institution of Hebei Province, Shijiazhuang, Hebei, China.
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Lv F, Cai X, Lin C, Yang W, Ji L. Effects of Semaglutide and Tirzepatide on Bone Metabolism in Type 2 Diabetic Mice. Pharmaceuticals (Basel) 2024; 17:1655. [PMID: 39770498 PMCID: PMC11728704 DOI: 10.3390/ph17121655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/30/2024] [Accepted: 12/06/2024] [Indexed: 01/16/2025] Open
Abstract
Background/Objectives: Type 2 diabetes and weight loss are associated with detrimental skeletal health. Incretin-based therapies (GLP-1 receptor agonists, and dual GIP/GLP-1 receptor agonists) are used clinically to treat diabetes and obesity. The potential effects of semaglutide and tirzepatide on bone metabolism in type 2 diabetic mice remain uncertain. Methods: Combined streptozotocin and high fat feeding were employed in female C57BL/6J mice to promote hyperglycemia. Mice were administered for 4 weeks with a saline vehicle (sc., once-daily), semaglutide (40 μg/kg/d, sc., every three days), or tirzepatide (10 nmol/kg, sc., once-daily). Bone strength was assessed by three-point bending. Femur microarchitecture was determined by micro-CT, and bone formation and resorption parameters were measured by histomorphometric analysis. Serum was collected to measure bone resorption (C-telopeptide fragments of type I collagen, CTX) and formation (procollagen type 1 N-terminal propeptide, P1NP) biomarkers, respectively. The expression of bone metabolism-related genes was evaluated in the bone using RT-PCR. Results: Glucose levels significantly reduced after 4 weeks of semaglutide and tirzepatide treatment (both p < 0.05) compared with vehicle treatment. Tirzepatide led to more weight loss than semaglutide. Compared to saline-treated diabetic mice, the mean femur length was shorter in the tirzepatide group. After treatment with tirzepatide or semaglutide, cortical bone and trabecular bone parameters did not change significantly compared to saline-treated diabetic mice, except that cortical thickness was lower in the semaglutide group compared to the saline group (p = 0.032). Though CTX and P1NP levels decreased, however, the change in CTX and P1NP levels did not differ among the four groups during the 4 weeks of treatment (all p > 0.05). Semaglutide affected RANKL and OPG mRNA expression and increased the ratio of OPG/RANKL. No significant difference was found in the quantity of Col1a1, RANKL, OPG, and RUNX2 between tirzepatide- and saline-treated diabetic mice. Conclusions: The 4-week treatment with semaglutide and tirzepatide had a neutral effect on bone mass compared with the controls, and most of the bone microarchitecture parameters were also comparable between groups in diabetic mice. A better understanding of incretin-based therapies on bone metabolism in patients with diabetes requires further evaluation in large clinical trials.
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Affiliation(s)
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing 100044, China; (F.L.); (C.L.); (W.Y.)
| | | | | | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing 100044, China; (F.L.); (C.L.); (W.Y.)
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Agrawal V, Amasa S, Karabacak M, Margetis K. Perioperative Glucagon-Like Peptide-1 Agonist Use and Rates of Pseudarthrosis After Single-Level Lumbar Fusion: A Large Retrospective Cohort Study. Neurosurgery 2024:00006123-990000000-01452. [PMID: 39589142 DOI: 10.1227/neu.0000000000003291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 10/11/2024] [Indexed: 11/27/2024] Open
Abstract
BACKGROUND AND OBJECTIVE Pseudarthrosis is a common surgical complication after arthrodesis and is associated with poor clinical outcomes. The association between glucagon-like peptide-1 (GLP-1) agonist use and pseudarthrosis is yet to be explored. This study aims to examine the association of GLP-1 agonists with rates of pseudarthrosis in patients undergoing single-level lumbar fusion. METHODS This national multicenter cohort study used data spanning from June 19, 2010, to June 19, 2024, from the global health network TriNetX. One-to-one propensity score matching for age, sex, race, comorbidities, body mass index, and A1c was conducted to balance cohorts. The rates of pseudarthrosis were then assessed within the 6-month, 1-year, and 2-year postsurgical follow-up periods. RESULTS A total of 37 147 patients who underwent single-level lumbar fusion (mean [SD] age, 59.3 [13.5] years; 47.7% men and 52.3% women) were enrolled in the study. Among these, 712 individuals (1.9%) were identified as GLP-1 agonist users. After propensity score matching, there were 709 patients in each cohort. Patients who took a GLP-1 agonist had lower odds of developing pseudarthrosis 6 months [odds ratio (OR): 0.70, 95% CI: 0.51-0.96], 1 year [OR: 0.68, 95% CI: 0.50-0.91], and 2 years (OR: 0.68, 95% CI: 0.50-0.91) after a posterior lumbar interbody fusion/transforaminal lumbar interbody fusion procedure. CONCLUSION In this cohort study, patients who were prescribed GLP-1 agonists in the perioperative period had reduced rates of pseudarthrosis compared with patients without GLP-1 agonist prescriptions. These findings suggest a potential therapeutic benefit of GLP-1 agonists in enhancing spinal fusion outcomes and warrant further prospective studies to confirm these results and explore the underlying mechanisms.
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Affiliation(s)
- Vedant Agrawal
- University of Texas Medical Branch John Sealy School of Medicine, Galveston, Texas, USA
| | - Saketh Amasa
- University of Texas Medical Branch John Sealy School of Medicine, Galveston, Texas, USA
| | - Mert Karabacak
- Department of Neurosurgery, Mount Sinai Health System, New York, New York, USA
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Xiao Y, Zhou M, Xiao W. Fracture events associated with GLP-1 receptor agonists in FDA adverse events reporting system. Acta Diabetol 2024:10.1007/s00592-024-02415-w. [PMID: 39556224 DOI: 10.1007/s00592-024-02415-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 11/10/2024] [Indexed: 11/19/2024]
Abstract
AIMS Diabetes patients are at a higher risk of fractures, and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been suggested to positively impact on bone metabolism. We aim to provide a comprehensive assessment of fracture events associated with GLP-1RAs based on pharmacovigilance data. METHODS In this study, fracture-related adverse events (AEs) associated with GLP-1RAs and other commonly used glucose-lowering drugs were identified from Food and Drug Administration Adverse Event Reporting System (FAERS) database (2004-2022). The reporting odds ratio (ROR) and adjusted ROR (adj. ROR) were used to compare the reporting of fracture-related AEs associated with insulin, GLP-1RAs, and Non GLP-1RAs, in patients with diabetes through two scenarios. This involved separately comparing each glucose-lowering drug to all other medications used in diabetic patients and reiterating after excluding insulin cases. RESULTS A total of 490,107 AE reports for patients with diabetes were identified and 98, 625 of them were for GLP-1RAs. Among all diabetes drugs, GLP-1RAs had the lowest reporting of any fracture-related AEs [adj. ROR = 0.44 (0.40-0.47)], consistent across osteoporotic fracture [adj. ROR = 0.39 (0.34-0.45)] and hip fracture [adj. ROR = 0.34 (0.28-0.41)]. Among GLP-1RA agents, albiglutide was associated with the lowest adj. ROR [0.11 (0.05-0.21)] for any fracture-related AEs. After excluded all insulin reports, GLP-1RAs retained a significantly lower adj. ROR towards any fracture [adj. ROR = 0.45 (0.40-0.50)], osteoporotic fracture [adj. ROR = 0.44 (0.37-0.52)], and hip fracture [adj. ROR = 0.43 (0.33-0.54)]. CONCLUSION In a real-world pharmacovigilance setting, GLP-1RAs were associated with lower reporting of fracture-related AEs, indicating the protective effect of GLP-1RAs against fractures.
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Affiliation(s)
- Yao Xiao
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China
| | - Min Zhou
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China
| | - Wenfeng Xiao
- Department of Orthopedics, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, China.
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Chen Z, Wang Y, Zhang G, Zheng J, Tian L, Song Y, Liu X. Role of LRP5/6/GSK-3β/β-catenin in the differences in exenatide- and insulin-promoted T2D osteogenesis and osteomodulation. Br J Pharmacol 2024; 181:3556-3575. [PMID: 38804080 DOI: 10.1111/bph.16421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 04/10/2024] [Accepted: 04/15/2024] [Indexed: 05/29/2024] Open
Abstract
BACKGROUND AND PURPOSE Insulin and exenatide are two hypoglycaemic agents that exhibit different osteogenic effects. This study compared the differences between exenatide and insulin in osseointegration in a rat model of Type 2 diabetes (T2D) and explored the mechanisms promoting osteogenesis in this model of T2D. EXPERIMENTAL APPROACH In vivo, micro-CT was used to detect differences in the peri-implant bone microstructure in vivo. Histology, dual-fluorescent labelling, immunofluorescence and immunohistochemistry were used to detect differences in tissue, cell and protein expression around the implants. In vitro, RT-PCR and western blotting were used to measure the expression of osteogenesis- and Wnt signalling-related genes and proteins in bone marrow mesenchymal stromal cells (BMSCs) from rats with T2D (TBMSCs) after PBS, insulin and exenatide treatment. RT-PCR was used to detect the expression of Wnt bypass cascade reactions under Wnt inactivation. KEY RESULTS Micro-CT and section staining showed exenatide extensively promoted peri-implant osseointegration. Both in vivo and in vitro experiments showed exenatide substantially increased the expression of osteogenesis-related and activated the LRP5/6/GSK-3β/β-catenin-related Wnt pathway. Furthermore, exenatide suppressed expression of Bmpr1a to inhibit lipogenesis and promoted expression of Btrc to suppress inflammation. CONCLUSION AND IMPLICATIONS Compared to insulin, exenatide significantly improved osteogenesis in T2D rats and TBMSCs. In addition to its dependence on LRP5/6/GSK-3β/β-catenin signalling for osteogenic differentiation, exenatide-mediated osteomodulation also involves inhibition of inflammation and adipogenesis by BMPR1A and β-TrCP, respectively.
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Affiliation(s)
- Zijun Chen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, Air Force Medical University, Xi'an, China
| | - Yuxi Wang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, Air Force Medical University, Xi'an, China
| | - Guanhua Zhang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, Air Force Medical University, Xi'an, China
| | - Jian Zheng
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, Air Force Medical University, Xi'an, China
| | - Lei Tian
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, Air Force Medical University, Xi'an, China
| | - Yingliang Song
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, Air Force Medical University, Xi'an, China
| | - Xiangdong Liu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, Air Force Medical University, Xi'an, China
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Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C, Gao J. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct Target Ther 2024; 9:234. [PMID: 39289339 PMCID: PMC11408715 DOI: 10.1038/s41392-024-01931-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 06/17/2024] [Accepted: 07/16/2024] [Indexed: 09/19/2024] Open
Abstract
The glucagon-like peptide-1 (GLP-1) receptor, known as GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family and is found primarily on the surfaces of various cell types within the human body. This receptor specifically interacts with GLP-1, a key hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, and several other crucial biological functions. In recent years, GLP-1 medications have become a focal point in the medical community due to their innovative treatment mechanisms, significant therapeutic efficacy, and broad development prospects. This article thoroughly traces the developmental milestones of GLP-1 drugs, from their initial discovery to their clinical application, detailing the evolution of diverse GLP-1 medications along with their distinct pharmacological properties. Additionally, this paper explores the potential applications of GLP-1 receptor agonists (GLP-1RAs) in fields such as neuroprotection, anti-infection measures, the reduction of various types of inflammation, and the enhancement of cardiovascular function. It provides an in-depth assessment of the effectiveness of GLP-1RAs across multiple body systems-including the nervous, cardiovascular, musculoskeletal, and digestive systems. This includes integrating the latest clinical trial data and delving into potential signaling pathways and pharmacological mechanisms. The primary goal of this article is to emphasize the extensive benefits of using GLP-1RAs in treating a broad spectrum of diseases, such as obesity, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases, musculoskeletal inflammation, and various forms of cancer. The ongoing development of new indications for GLP-1 drugs offers promising prospects for further expanding therapeutic interventions, showcasing their significant potential in the medical field.
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Affiliation(s)
- Zhikai Zheng
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yao Zong
- Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia
| | - Yiyang Ma
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yucheng Tian
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yidan Pang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Changqing Zhang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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Kim HJ, Choi SA, Gu MS, Ko SY, Kwon JH, Han JY, Kim JH, Kim MG. Effects of Glucagon-Like Peptide-1 Receptor Agonist on Bone Mineral Density and Bone Turnover Markers: A Meta-Analysis. Diabetes Metab Res Rev 2024; 40:e3843. [PMID: 39311048 DOI: 10.1002/dmrr.3843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/19/2024] [Accepted: 09/04/2024] [Indexed: 10/15/2024]
Abstract
AIMS Glucagon-like peptide-1 receptor agonist (GLP-1RA) may promote bone formation, but conversely, they could also weaken bones due to the reduction in mechanical load associated with weight loss. However, the clinical effects in humans have not been clearly demonstrated. This meta-analysis aimed to evaluate whether GLP-1RAs affect BMD and bone turnover markers. MATERIAL AND METHODS PubMed, Embase, and Scopus were searched on June 13, 2024. The eligibility criteria were: (1) human studies, (2) receiving a GLP-1RA for more than 4 weeks, (3) an untreated control group or a placebo group, (4) reporting of at least one BMD or bone turnover marker, and (5) an RCT design. The risk of bias was assessed using the Cochrane risk of bias 2 tool. Fixed- or random-effects meta-analysis was performed according to heterogeneity. RESULTS Seven studies were included in the meta-analysis. GLP-1RAs did not significantly change BMD in the femoral neck (mean difference [MD], 0.01 g/cm2; 95% CI, -0.01-0.04 g/cm2), in the total hip (MD, -0.01 g/cm2; 95% CI, -0.02-0.01 g/cm2), and in the lumbar spine (MD, 0 g/cm2; 95% CI, -0.02-0.02 g/cm2). C-terminal telopeptide of type 1 collagen (CTX), a bone resorption marker, significantly increased after GLP-1RA treatment (MD, 0.04 μg/L; 95% CI, 0.01-0.07 μg/L). GLP-1RAs did not significantly change bone formation markers such as procollagen type 1 N-terminal propeptide, bone-specific alkaline phosphatase, osteocalcin. CONCLUSIONS GLP-1RA did not affect BMD and bone formation markers. However, GLP-1RAs led to a significant increase in CTX.
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Affiliation(s)
- Hee-Ju Kim
- College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Seo-A Choi
- College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Min-Sun Gu
- College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Seo-Yeong Ko
- College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Jae-Hee Kwon
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Ja-Young Han
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Jae Hyun Kim
- School of Pharmacy and Institute of New Drug Development, Jeonbuk National University, Jeonju, Republic of Korea
| | - Myeong Gyu Kim
- College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea
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10
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Leungsuwan DS, Chandran M. Bone Fragility in Diabetes and its Management: A Narrative Review. Drugs 2024; 84:1111-1134. [PMID: 39103693 DOI: 10.1007/s40265-024-02078-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 08/07/2024]
Abstract
Bone fragility is a serious yet under-recognised complication of diabetes mellitus (DM) that is associated with significant morbidity and mortality. Multiple complex pathophysiological mechanisms mediating bone fragility amongst DM patients have been proposed and identified. Fracture risk in both type 1 diabetes (T1D) and type 2 diabetes (T2D) continues to be understated and underestimated by conventional risk assessment tools, posing an additional challenge to the identification of at-risk patients who may benefit from earlier intervention or preventive strategies. Over the years, an increasing body of evidence has demonstrated the efficacy of osteo-pharmacological agents in managing skeletal fragility in DM. This review seeks to elaborate on the risk of bone fragility in DM, the underlying pathogenesis and skeletal alterations, the approach to fracture risk assessment in DM, management strategies and therapeutic options.
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Affiliation(s)
| | - Manju Chandran
- Osteoporosis and Bone Metabolism Unit, Department of Endocrinology, Singapore General Hospital, 20 College Road, ACADEMIA, Singapore, 169856, Singapore.
- DUKE NUS Medical School, Singapore, Singapore.
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11
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Alenezi BT, Elfezzani N, Uddin R, Patel H, Chester S, Abdelmaksoud A, Hussein MH, Zaitone SA, Fawzy MS, Aiash H, Toraih EA. Beyond Glycemic Control: GLP-1 Receptor Agonists and Their Impact on Calcium Homeostasis in Real-World Patients. J Clin Med 2024; 13:4896. [PMID: 39201039 PMCID: PMC11355112 DOI: 10.3390/jcm13164896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 08/11/2024] [Accepted: 08/18/2024] [Indexed: 09/02/2024] Open
Abstract
Background/Objectives: The effect of glucagon-like peptide-1 receptor (GLP-1R) agonists on calcium homeostasis is poorly understood. This study aimed to investigate the association between GLP-1R agonist use and the risk of hypocalcemia and/or hypercalcemia, as well as other clinical outcomes. Methods: A retrospective cohort study used de-identified patient data from the TriNetX Global Collaborative Network, including 15,655 adult patients prescribed GLP-1R agonists and 15,655 propensity-matched controls. Outcomes included hypocalcemia, hypercalcemia, emergency visits, hospitalizations, cardiovascular events, and all-cause mortality. Results: GLP-1R agonist use was associated with a reduced risk of hypocalcemia (2.7% vs. 5.5%, RR 0.49, 95% CI: 0.44-0.55) but an increased risk of hypercalcemia (2.3% vs. 1.1%, RR 2.02, 95% CI: 1.69-2.42). The effect on hypocalcemia was most pronounced during the first six months of treatment. Among individual agents, tirzepatide showed the most pronounced effect, reducing hypocalcemia risk by 63% while increasing hypercalcemia risk by 85%. Semaglutide demonstrated similar effects, while dulaglutide and liraglutide showed modest effects. Furthermore, GLP-1R agonist use was associated with reduced risks of emergency visits (RR 0.57, 95% CI: 0.54-0.60), hospitalizations (RR 0.40, 95% CI: 0.36-0.44), cardiovascular events, and all-cause mortality (HR 0.27, 95% CI: 0.21-0.36). Conclusions: GLP-1R agonists exhibit a complex influence on calcium homeostasis, reducing hypocalcemia risk while increasing hypercalcemia risk. Beyond calcium regulation, these medications significantly reduce healthcare utilization, improve cardiovascular outcomes, and decrease mortality. Further research is needed to elucidate the mechanisms behind the differential effects of individual GLP-1R agonists, particularly tirzepatide, to optimize personalized treatment approaches and long-term safety.
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Affiliation(s)
- Bandar T. Alenezi
- Department of Pharmacology, Faculty of Medicine, Northern Border University, Arar 91431, Saudi Arabia;
| | - Nadra Elfezzani
- Tulane School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA;
| | - Rukhsana Uddin
- Women Medical and Dental College, Khyber Medical University Peshawar, Abbottabad 22080, Pakistan;
| | - Hinali Patel
- School of Medicine, Louisiana State University, New Orleans, LA 70112, USA;
| | - Sydney Chester
- School of Medicine, Tulane University, New Orleans, LA 70112, USA;
| | - Ahmed Abdelmaksoud
- Department of Internal Medicine, University of California, Riverside, CA 92521, USA;
| | - Mohammad H. Hussein
- Department of Family Medicine, Ochsner Clinic Foundation, New Orleans, LA 70112, USA;
| | - Sawsan A. Zaitone
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Manal S. Fawzy
- Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar 91431, Saudi Arabia
- Center for Health Research, Northern Border University, Arar 91431, Saudi Arabia
| | - Hani Aiash
- SUNY Upstate Medical University, Syracuse, NY 13210, USA;
| | - Eman A. Toraih
- Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA
- Medical Genetics Unit, Department of Histology and Cell Biology, Suez Canal University, Ismailia 41522, Egypt
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12
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Mabilleau G, Bouvard B. Gut hormone analogues and skeletal health in diabetes and obesity: Evidence from preclinical models. Peptides 2024; 177:171228. [PMID: 38657908 DOI: 10.1016/j.peptides.2024.171228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 04/17/2024] [Accepted: 04/22/2024] [Indexed: 04/26/2024]
Abstract
Diabetes mellitus and obesity are rapidly growing worldwide. Aside from metabolic disturbances, these two disorders also affect bone with a higher prevalence of bone fractures. In the last decade, a growing body of evidence suggested that several gut hormones, including ghrelin, gastrin, glucose-dependent insulinotropic polypeptide (GIP), glucagon, and glucagon-like peptide-1 and 2 (GLP-1 and GLP-2, respectively) may affect bone physiology. Several gut hormone analogues have been developed for the treatment of type 2 diabetes and obesity, and could represent a new alternative in the therapeutic arsenal against bone fragility. In the present review, a summary of the physiological roles of these gut hormones and their analogues is presented at the cellular level but also in several preclinical models of bone fragility disorders including type 2 diabetes mellitus, especially on bone mineral density, microarchitecture and bone material properties. The present review also summarizes the impact of GLP-1 receptor agonists approved for the treatment of type 2 diabetes mellitus and the more recent dual or triple analogue on bone physiology and strength.
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Affiliation(s)
- Guillaume Mabilleau
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS, UMR 1229, SFR ICAT, Angers F-49000, France; CHU Angers, Département de Pathologie Cellulaire et Tissulaire, UF de Pathologie osseuse, Angers F-49933, France.
| | - Béatrice Bouvard
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS, UMR 1229, SFR ICAT, Angers F-49000, France; CHU Angers, Service de Rhumatologie, Angers F-49933, France
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13
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Bouvard B, Mabilleau G. Gut hormones and bone homeostasis: potential therapeutic implications. Nat Rev Endocrinol 2024:10.1038/s41574-024-01000-z. [PMID: 38858581 DOI: 10.1038/s41574-024-01000-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/14/2024] [Indexed: 06/12/2024]
Abstract
Bone resorption follows a circadian rhythm, with a marked reduction in circulating markers of resorption (such as carboxy-terminal telopeptide region of collagen type I in serum) in the postprandial period. Several gut hormones, including glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and GLP2, have been linked to this effect in humans and rodent models. These hormones are secreted from enteroendocrine cells in the gastrointestinal tract in response to a variety of stimuli and effect a wide range of physiological processes within and outside the gut. Single GLP1, dual GLP1-GIP or GLP1-glucagon and triple GLP1-GIP-glucagon receptor agonists have been developed for the treatment of type 2 diabetes mellitus and obesity. In addition, single GIP, GLP1 and GLP2 analogues have been investigated in preclinical studies as novel therapeutics to improve bone strength in bone fragility disorders. Dual GIP-GLP2 analogues have been developed that show therapeutic promise for bone fragility in preclinical studies and seem to exert considerable activity at the bone material level. This Review summarizes the evidence of the action of gut hormones on bone homeostasis and physiology.
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Affiliation(s)
- Béatrice Bouvard
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS UMR 1229, Angers, France
- CHU Angers, Service de Rhumatologie, Angers, France
| | - Guillaume Mabilleau
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS UMR 1229, Angers, France.
- CHU Angers, Departement de Pathologie Cellulaire et Tissulaire, Angers, France.
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14
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Hansen MS, Wölfel EM, Jeromdesella S, Møller JJK, Ejersted C, Jørgensen NR, Eastell R, Hansen SG, Frost M. Once-weekly semaglutide versus placebo in adults with increased fracture risk: a randomised, double-blinded, two-centre, phase 2 trial. EClinicalMedicine 2024; 72:102624. [PMID: 38737002 PMCID: PMC11087719 DOI: 10.1016/j.eclinm.2024.102624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 04/08/2024] [Accepted: 04/16/2024] [Indexed: 05/14/2024] Open
Abstract
Background Previous studies have indicated that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) may enhance bone formation and have neutral or beneficial effects on fracture risk. We evaluated the effect of the GLP-1RA semaglutide on the bone formation marker Procollagen type I N-terminal propeptide (PINP) in adults with increased fracture risk. Methods This randomised, placebo-controlled, double-blinded, phase 2 clinical trial was conducted at two public hospitals in Denmark. We enrolled 64 men and women with increased fracture risk based on a T-score < -1.0 at the total hip or lumbar spine and/or low-energy fracture within three years of recruitment. Participants were randomised (1:1) to receive once-weekly subcutaneous semaglutide 1.0 mg or placebo. The primary outcome was changes in plasma (P)-PINP from baseline to week 52. Primary and safety outcomes were assessed and evaluated for all participants. This trial is complete and registered with ClinicalTrials.gov, NCT04702516. Findings Between March 24 and December 8, 2021, 55 (86%) postmenopausal women and nine men with a mean age of 63 years (SD 5.5) and BMI of 27.5 kg/m2 (SD 4.5) were enrolled. There was no effect on changes in P-PINP from baseline to week 52 between the two groups (estimated treatment difference (ETD) semaglutide versus placebo 3.8 μg/L [95% CI -5.6 to 13.3]; p = 0.418), and no difference in P-PINP levels between groups at week 52 (semaglutide 64.3 μg/L versus placebo 62.3 μg/L [95% CI -10.8 to 15.0]; p = 0.749). The secondary outcomes showed higher plasma levels of bone resorption marker Collagen type I cross-linked C-terminal telopeptide (P-CTX) in the semaglutide group than in the placebo group (ETD 166.4 ng/L [95% CI 25.5-307.3]; p = 0.021). Compared to placebo, lumbar spine and total hip areal bone mineral densities (aBMD) were lower in the semaglutide group after 52 weeks ((ETD lumbar spine -0.018 g/cm3 [95% CI -0.031 to -0.005]; p = 0.007); ETD total hip -0.020 g/cm2 ([95% CI -0.032 to -0.008]; p = 0.001). Treatment differences in femoral neck aBMD were not observed ([95% CI [-0.017 to 0.006]; p = 0.328). Further, body weight was lower in the semaglutide group than in the placebo group after 52 weeks (ETD -6.8 kg [95% CI -8.8 to -4.7]; p < 0.001). Thirty-one [97%] in the semaglutide group and 18 [56%] in the placebo group experienced at least one adverse event, including four serious events (two in each group). No episodes of hypoglycaemia or deaths were reported. Interpretation In adults with increased fracture risk, semaglutide once weekly did not increase bone formation based on the bone formation marker P-PINP. The observed increase in bone resorption in the semaglutide group may be explained by the accompanying weight loss. Funding Region of Southern Denmark, Novo Nordisk Foundation, and Gangsted Foundation. Novo Nordisk provided the investigational drug and placebo.
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Affiliation(s)
- Morten S. Hansen
- Department of Endocrinology, Odense University Hospital, Denmark
- Clinical Institute, Faculty of Health Sciences, University of Southern Denmark, Denmark
| | - Eva M. Wölfel
- Clinical Institute, Faculty of Health Sciences, University of Southern Denmark, Denmark
| | - Shakespeare Jeromdesella
- Department of Endocrinology, Odense University Hospital, Denmark
- Clinical Institute, Faculty of Health Sciences, University of Southern Denmark, Denmark
| | - Jens-Jakob K. Møller
- Open Patient Data Explorative Network (OPEN), Odense University Hospital, Denmark
| | | | - Niklas R. Jørgensen
- Department of Clinical Biochemistry, Rigshospitalet, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Richard Eastell
- Division of Clinical Medicine, University of Sheffield, Sheffield, United Kingdom
| | - Stinus G. Hansen
- Department of Diabetes and Endocrinology, Esbjerg Hospital, University Hospital of Southern Denmark, Denmark
| | - Morten Frost
- Department of Endocrinology, Odense University Hospital, Denmark
- Clinical Institute, Faculty of Health Sciences, University of Southern Denmark, Denmark
- Steno Diabetes Centre Odense, Odense University Hospital, Denmark
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15
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IIDA M, ASANO A. Effects of glucagon-like peptide-1 receptor agonists on spermatogenesis-related gene expression in mouse testis and testis-derived cell lines. J Vet Med Sci 2024; 86:555-562. [PMID: 38556323 PMCID: PMC11144540 DOI: 10.1292/jvms.24-0042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 03/13/2024] [Indexed: 04/02/2024] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin released into the gastrointestinal tract after food ingestion, and stimulates insulin secretion from the beta cells of the pancreatic islets. Incretins have recently been reported to have extrapancreatic actions, and they are anticipated to have potential efficacy for conditions such as male infertility as well as diabetes. However, the effects of incretins on male reproductive function remain unclear. In this study, GLP-1 receptor expression and the effects of GLP-1 on spermatogenesis-associated genes were investigated using mouse testes and testis-derived cultured cell lines. Glp1r mRNA and GLP-1 protein were expressed in mouse testes at levels comparable to or greater than those in positive control adipose tissue, and the liver and intestine, and also in a Sertoli cell line (TM4) and a Leydig cell line (MA-10) as well as the GC-1 spg and GC-2 spd (ts) germ cell lines. TM4 cells treated with the GLP-1 receptor agonist exenatide showed transiently and significantly upregulated Kitl, Pdgfa, and Glp1r mRNA expression. Furthermore, at 1 hr post-exenatide administration to male mice, Kitl and Glp1r mRNA expression levels were significantly increased, and Pdgfa mRNA expression level also showed a tendency toward increase. TM4 cells were treated with various cell-activating agents, and bucladesine elicited significantly increased Glp1r mRNA expression. We suggest that GLP-1 provides acute stimulation of Sertoli cells in the mouse testis and has a stimulatory effect on the expression of spermatogenesis-related genes.
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Affiliation(s)
- Masashi IIDA
- Laboratory of Laboratory Animal Science, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan
- Safety Assessment Department, Kumamoto Laboratories, Mediford Corporation, Tokyo, Japan
| | - Atsushi ASANO
- Laboratory of Laboratory Animal Science, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan
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16
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Forner P, Sheu A. Bone Health in Patients With Type 2 Diabetes. J Endocr Soc 2024; 8:bvae112. [PMID: 38887632 PMCID: PMC11181004 DOI: 10.1210/jendso/bvae112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Indexed: 06/20/2024] Open
Abstract
The association between type 2 diabetes mellitus (T2DM) and skeletal fragility is complex, with effects on bone at the cellular, molecular, and biomechanical levels. As a result, people with T2DM, compared to those without, are at increased risk of fracture, despite often having preserved bone mineral density (BMD) on dual-energy x-ray absorptiometry (DXA). Maladaptive skeletal loading and changes in bone architecture (particularly cortical porosity and low cortical volumes, the hallmark of diabetic osteopathy) are not apparent on routine DXA. Alternative imaging modalities, including quantitative computed tomography and trabecular bone score, allow for noninvasive visualization of cortical and trabecular compartments and may be useful in identifying those at risk for fractures. Current fracture risk calculators underestimate fracture risk in T2DM, partly due to their reliance on BMD. As a result, individuals with T2DM, who are at high risk of fracture, may be overlooked for commencement of osteoporosis therapy. Rather, management of skeletal health in T2DM should include consideration of treatment initiation at lower BMD thresholds, the use of adjusted fracture risk calculators, and consideration of metabolic and nonskeletal risk factors. Antidiabetic medications have differing effects on the skeleton and treatment choice should consider the bone impacts in those at risk for fracture. T2DM poses a unique challenge when it comes to assessing bone health and fracture risk. This article discusses the clinical burden and presentation of skeletal disease in T2DM. Two clinical cases are presented to illustrate a clinical approach in assessing and managing fracture risk in these patients.
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Affiliation(s)
- Patrice Forner
- Clinical School, Faculty of Medicine, St Vincent's Hospital, University of New South Wales Sydney, Sydney, NSW 2010, Australia
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, NSW 2010, Australia
| | - Angela Sheu
- Clinical School, Faculty of Medicine, St Vincent's Hospital, University of New South Wales Sydney, Sydney, NSW 2010, Australia
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, NSW 2010, Australia
- Skeletal Diseases Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2035, Australia
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17
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Liu H, Xiao H, Lin S, Zhou H, Cheng Y, Xie B, Xu D. Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis. Front Pharmacol 2024; 15:1372399. [PMID: 38725663 PMCID: PMC11079205 DOI: 10.3389/fphar.2024.1372399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 03/25/2024] [Indexed: 05/12/2024] Open
Abstract
Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night. This circadian rhythm of the skeleton is regulated by gut hormones. Until now, gut hormones that have been found to affect skeletal homeostasis include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), and peptide YY (PYY), which exerts its effects by binding to its cognate receptors (GLP-1R, GLP-2R, GIPR, and Y1R). Several studies have shown that GLP-1, GLP-2, and GIP all inhibit bone resorption, while GIP also promotes bone formation. Notably, PYY has a strong bone resorption-promoting effect. In addition, gut microbiota (GM) plays an important role in maintaining bone homeostasis. This review outlines the roles of GLP-1, GLP-2, GIP, and PYY in bone metabolism and discusses the roles of gut hormones and the GM in regulating bone homeostasis and their potential mechanisms.
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Affiliation(s)
- Hongyu Liu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Huimin Xiao
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Sufen Lin
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Huan Zhou
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Yizhao Cheng
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Baocheng Xie
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Department of Pharmacy, The 10th Affiliated Hospital of Southern Medical University (Dongguan People’s Hospital), Dongguan, China
| | - Daohua Xu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
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18
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He Z, Li H, Zhang Y, Gao S, Liang K, Su Y, Du Y, Wang D, Xing D, Yang Z, Lin J. Enhanced bone regeneration via endochondral ossification using Exendin-4-modified mesenchymal stem cells. Bioact Mater 2024; 34:98-111. [PMID: 38186959 PMCID: PMC10770633 DOI: 10.1016/j.bioactmat.2023.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 12/05/2023] [Accepted: 12/06/2023] [Indexed: 01/09/2024] Open
Abstract
Nonunions and delayed unions pose significant challenges in orthopedic treatment, with current therapies often proving inadequate. Bone tissue engineering (BTE), particularly through endochondral ossification (ECO), emerges as a promising strategy for addressing critical bone defects. This study introduces mesenchymal stem cells overexpressing Exendin-4 (MSC-E4), designed to modulate bone remodeling via their autocrine and paracrine functions. We established a type I collagen (Col-I) sponge-based in vitro model that effectively recapitulates the ECO pathway. MSC-E4 demonstrated superior chondrogenic and hypertrophic differentiation and enhanced the ECO cell fate in single-cell sequencing analysis. Furthermore, MSC-E4 encapsulated in microscaffold, effectively facilitated bone regeneration in a rat calvarial defect model, underscoring its potential as a therapeutic agent for bone regeneration. Our findings advocate for MSC-E4 within a BTE framework as a novel and potent approach for treating significant bone defects, leveraging the intrinsic ECO process.
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Affiliation(s)
- Zihao He
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, 100044, China
- Arthritis Institute, Peking University, Beijing, 100044, China
| | - Hui Li
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, 100044, China
- Arthritis Institute, Peking University, Beijing, 100044, China
| | - Yuanyuan Zhang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, 100084, China
| | - Shuang Gao
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, 100084, China
| | - Kaini Liang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, 100084, China
| | - Yiqi Su
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, 100044, China
- Arthritis Institute, Peking University, Beijing, 100044, China
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, 100084, China
| | - Du Wang
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, 100044, China
- Arthritis Institute, Peking University, Beijing, 100044, China
| | - Dan Xing
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, 100044, China
- Arthritis Institute, Peking University, Beijing, 100044, China
| | - Zhen Yang
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, 100044, China
- Arthritis Institute, Peking University, Beijing, 100044, China
| | - Jianhao Lin
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, 100044, China
- Arthritis Institute, Peking University, Beijing, 100044, China
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19
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Ali A, Flatt PR, Irwin N. Gut-Derived Peptide Hormone Analogues and Potential Treatment of Bone Disorders in Obesity and Diabetes Mellitus. Clin Med Insights Endocrinol Diabetes 2024; 17:11795514241238059. [PMID: 38486712 PMCID: PMC10938612 DOI: 10.1177/11795514241238059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 02/14/2024] [Indexed: 03/17/2024] Open
Abstract
Obesity and diabetes mellitus are prevalent metabolic disorders that have a detrimental impact on overall health. In this regard, there is now a clear link between these metabolic disorders and compromised bone health. Interestingly, both obesity and diabetes lead to elevated risk of bone fracture which is independent of effects on bone mineral density (BMD). In this regard, gastrointestinal (GIT)-derived peptide hormones and their related long-acting analogues, some of which are already clinically approved for diabetes and/or obesity, also seem to possess positive effects on bone remodelling and microarchitecture to reduce bone fracture risk. Specifically, the incretin peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as glucagon-like peptide-2 (GLP-2), exert key direct and/or indirect benefits on bone metabolism. This review aims to provide an initial appraisal of the relationship between obesity, diabetes and bone, with a focus on the positive impact of these GIT-derived peptide hormones for bone health in obesity/diabetes. Brief discussion of related peptides such as parathyroid hormone, leptin, calcitonin and growth hormone is also included. Taken together, drugs engineered to promote GIP, GLP-1 and GLP-2 receptor signalling may have potential to offer therapeutic promise for improving bone health in obesity and diabetes.
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Affiliation(s)
- Asif Ali
- Diabetes Research Centre, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, UK
| | - Peter R Flatt
- Diabetes Research Centre, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, UK
| | - Nigel Irwin
- Diabetes Research Centre, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, UK
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20
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Gheonea TC, Șurlin P, Nicolae FM, Gheorghe DN, Popescu DM, Rogoveanu I. Dipeptidyl-Peptidase-4 and Glucagon-like-Peptide-1, a Link in the Connection between Periodontitis and Diabetes Mellitus-What Do We Know So Far?-A Scoping Review. J Clin Med 2024; 13:903. [PMID: 38337597 PMCID: PMC10856081 DOI: 10.3390/jcm13030903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/01/2024] [Accepted: 02/02/2024] [Indexed: 02/12/2024] Open
Abstract
Periodontitis is a common condition affecting the tissues surrounding and supporting teeth. In addition to oral health concerns, periodontal disease increases the chance of developing systemic illnesses including type 2 diabetes mellitus. Porphyromonas gingivalis, a key-stone pathogen that has been linked to the pathophysiology of periodontal disease, can generate a series of dipeptide producing exopeptidases, dipeptidyl peptidases (DPP). DPP-4 levels in gingival crevicular fluid have been shown to increase during active periodontal disease, which may lead to their association with the disease's progression. Following oral glucose administration, mice injected with DPP-4 had higher blood glucose than the control group. DPP-4 inhibitors are used to treat patients with type 2 diabetes mellitus in order to extend the half-life of incretins. Elevated glucagon-like peptide-1 (GLP-1) levels following periodontal therapy could be considered new and applicable real-world evidence confirming the experimental findings of a beneficial interaction between oral microbiota and incretin axis. GLP-1 receptor agonist exendin-4 enhanced the osteoblast proliferation and development of these stem cells and inhibited the effects of glucose on the cells. In addition to lowering blood sugar, liraglutide, a GLP-1 receptor agonist, also possesses anti-inflammatory and bone-protective properties. These findings support the use of GLP-1 in the management and prevention of diabetic periodontitis.
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Affiliation(s)
- Theodora Claudia Gheonea
- Center for IBD Patients, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200345 Craiova, Romania
| | - Petra Șurlin
- Department of Periodontology, Research Center of Periodontal-Systemic Interactions, Faculty of Dental Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania (D.M.P.)
| | - Flavia Mirela Nicolae
- Department of Periodontology, Research Center of Periodontal-Systemic Interactions, Faculty of Dental Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania (D.M.P.)
| | - Dorin Nicolae Gheorghe
- Department of Periodontology, Research Center of Periodontal-Systemic Interactions, Faculty of Dental Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania (D.M.P.)
| | - Dora Maria Popescu
- Department of Periodontology, Research Center of Periodontal-Systemic Interactions, Faculty of Dental Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania (D.M.P.)
| | - Ion Rogoveanu
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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21
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Fathy MA, Anbaig A, Aljafil R, El-Sayed SF, Abdelnour HM, Ahmed MM, Abdelghany EMA, Alnasser SM, Hassan SMA, Shalaby AM. Effect of Liraglutide on Osteoporosis in a Rat Model of Type 2 Diabetes Mellitus: A Histological, Immunohistochemical, and Biochemical Study. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2023; 29:2053-2067. [PMID: 37832035 DOI: 10.1093/micmic/ozad102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/04/2023] [Accepted: 09/02/2023] [Indexed: 10/15/2023]
Abstract
Diabetic osteoporosis (DOP) is a diabetic complication associated with a significant disability rate. Liraglutide, a glucagon-like peptide-1 receptor agonist, is a promising and innovative drug for type 2 diabetes mellitus (T2DM), with potential therapeutic implications for bone disorders. This investigation examined the impact of liraglutide on osteoporosis in rats with T2DM and studied the influence of vitamin D receptor Bsm1 polymorphism on liraglutide-induced outcomes. Thirty rats were divided into control, T2DM induced by a combination of a high-fat diet and 25 mg/kg streptozotocin, and T2DM-liraglutide (T2DM treated with 0.4 mg/kg/day liraglutide) groups. After 8 weeks of liraglutide treatment, femurs and blood samples were obtained from all rats for subsequent investigations. Diabetes induced a remarkable rise in the serum levels of receptor activator of nuclear factor kappa B ligand (RANKL) and C-telopeptide of type I collagen (CTX-1) associated with a remarkable decline in osteocalcin and osteoprotegerin (OPG). Impaired bone architecture was also demonstrated by light and scanning electron microscopic study. The immune expression of OPG was down-regulated, while RANKL was up-regulated. Interestingly, the administration of liraglutide ameliorated the previous changes induced by diabetes mellitus. In conclusion, liraglutide can prevent DOP, mostly due to liraglutide's ability to increase bone growth, while inhibiting bone resorption.
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Affiliation(s)
- Maha Abdelhamid Fathy
- Department of Medical Physiology, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Amal Anbaig
- Department of Pathology, Faculty of Medicine, Benghazi University, Benghazi 16063, Libya
| | - Raja Aljafil
- Department of Pathology, Faculty of Medicine, Benghazi University, Benghazi 16063, Libya
| | - Sherein F El-Sayed
- Department of Medical Physiology, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Hanim Magdy Abdelnour
- Department of Medical Biochemistry, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Mona Mostafa Ahmed
- Department of Pathology, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Eman M A Abdelghany
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Sulaiman Mohammed Alnasser
- Department of Pharmacology and Toxicology, Unaizah College of Pharmacy, Qassim University, Buraydah 52571, Saudi Arabia
| | - Shaimaa Mohamed Abdelfattah Hassan
- Department of Histology and Cell Biology, Faculty of Medicine, Menoufi University, Shebin El Koum 32511, Egypt
- Department of Histology, College of Medicine, Batterjee Medical College, Abha 61961, Saudi Arabia
| | - Amany Mohamed Shalaby
- Department of Histology and Cell Biology, Faculty of Medicine, Tanta University, Tanta 31527, Egypt
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22
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Viggers R, Rasmussen NH, Vestergaard P. Effects of Incretin Therapy on Skeletal Health in Type 2 Diabetes-A Systematic Review. JBMR Plus 2023; 7:e10817. [PMID: 38025038 PMCID: PMC10652182 DOI: 10.1002/jbm4.10817] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/11/2023] [Accepted: 08/16/2023] [Indexed: 12/01/2023] Open
Abstract
Diabetes poses a significant risk to bone health, with Type 1 diabetes (T1D) having a more detrimental impact than Type 2 diabetes (T2D). The group of hormones known as incretins, which includes gastric inhibitory peptide (GIP) and glucagon-like peptide 1 (GLP-1), play a role in regulating bowel function and insulin secretion during feeding. GLP-1 receptor agonists (GLP-1 RAs) are emerging as the primary treatment choice in T2D, particularly when atherosclerotic cardiovascular disease is present. Dipeptidyl peptidase 4 inhibitors (DPP-4is), although less potent than GLP-1 RAs, can also be used. Additionally, GLP-1 RAs, either alone or in combination with GIP, may be employed to address overweight and obesity. Since feeding influences bone turnover, a relationship has been established between incretins and bone health. To explore this relationship, we conducted a systematic literature review following the PRISMA guidelines. While some studies on cells and animals have suggested positive effects of incretins on bone cells, turnover, and bone density, human studies have yielded either no or limited and conflicting results regarding their impact on bone mineral density (BMD) and fracture risk. The effect on fracture risk may vary depending on the choice of comparison drug and the duration of follow-up, which was often limited in several studies. Nevertheless, GLP-1 RAs may hold promise for people with T2D who have multiple fracture risk factors and poor metabolic control. Furthermore, a potential new area of interest is the use of GLP-1 RAs in fracture prevention among overweight and obese people. Based on this systematic review, existing evidence remains insufficient to support a positive or a superior effect on bone health to reduce fracture risk in people with T2D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Rikke Viggers
- Steno Diabetes Center North DenmarkAalborgDenmark
- Department of EndocrinologyAalborg University HospitalAalborgDenmark
| | | | - Peter Vestergaard
- Steno Diabetes Center North DenmarkAalborgDenmark
- Department of EndocrinologyAalborg University HospitalAalborgDenmark
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23
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Nasser MI, Stidsen JV, Højlund K, Nielsen JS, Eastell R, Frost M. Low Bone Turnover Associates With Lower Insulin Sensitivity in Newly Diagnosed Drug-Naïve Persons With Type 2 Diabetes. J Clin Endocrinol Metab 2023; 108:e371-e379. [PMID: 36718513 PMCID: PMC10271224 DOI: 10.1210/clinem/dgad043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 12/29/2022] [Accepted: 01/24/2023] [Indexed: 02/01/2023]
Abstract
CONTEXT Bone turnover markers (BTMs) are lower in type 2 diabetes mellitus (T2D). The relationships between bone turnover, β-cell function, and insulin sensitivity in T2D are uncertain. OBJECTIVE To investigate if fasting levels of BTMs in persons with T2D are associated with β-cell function or insulin sensitivity. METHODS We defined three T2D phenotypes, the insulinopenic (low β-cell function, high insulin sensitivity), the classical (low β-cell function, low insulin sensitivity), and the hyperinsulinemic (high β-cell function, low insulin sensitivity) phenotypes, in the Danish Centre for Strategic Research T2D cohort using the homeostatic model assessment. We selected age- and gender-matched subgroups to represent the three T2D phenotypes, yielding 326 glucose-lowering treatment-naïve persons with T2D. Median values of BTMs between the three T2D phenotypes were compared. Regression models were applied to assess the association between BTMs, β-cell function, and insulin sensitivity adjusted for potential confounders. RESULTS Median serum levels of procollagen type I N-terminal propeptide, C-terminal telopeptide of type I collagen, and osteocalcin were higher in the insulinopenic phenotype (52.3 μg/L, IQR 41.6, 63.3; 259.4 ng/L, IQR 163.4, 347.7; and 18.0 μg/L, IQR 14.4, 25.2, respectively) compared with the classical (41.4, IQR 31.0, 51.4; 150.4 IQR 103.5, 265.1; 13.1, IQR 10.0, 17.6, respectively) and the hyperinsulinemic (43.7, IQR 32.3, 57.3; 163.3, IQR 98.9, 273.1; 15.7 IQR 10.2, 20.8, respectively) phenotypes (all P < .01). These differences persisted after adjustment for age, sex, waist to hip ratio, or fasting plasma glucose (P < .01). CONCLUSION BTMs are lower in newly diagnosed persons with T2D characterized by low insulin sensitivity.
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Affiliation(s)
- Mohamad I Nasser
- Department of Endocrinology and Metabolism, Molecular Endocrinology Laboratory (KMEB), Odense University Hospital, Odense 5000, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense 5000, Denmark
- Steno Diabetes Center Odense, Odense University Hospital, Odense 5000, Denmark
| | - Jacob V Stidsen
- Steno Diabetes Center Odense, Odense University Hospital, Odense 5000, Denmark
| | - Kurt Højlund
- Department of Clinical Research, University of Southern Denmark, Odense 5000, Denmark
- Steno Diabetes Center Odense, Odense University Hospital, Odense 5000, Denmark
| | - Jens Steen Nielsen
- Department of Clinical Research, University of Southern Denmark, Odense 5000, Denmark
- Steno Diabetes Center Odense, Odense University Hospital, Odense 5000, Denmark
| | - Richard Eastell
- Academic Unit of Bone Metabolism, University of Sheffield, Sheffield S10, UK
- Mellanby Centre for Musculoskeletal Research, University of Sheffield, Sheffield S10, UK
| | - Morten Frost
- Department of Endocrinology and Metabolism, Molecular Endocrinology Laboratory (KMEB), Odense University Hospital, Odense 5000, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense 5000, Denmark
- Steno Diabetes Center Odense, Odense University Hospital, Odense 5000, Denmark
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Xing B, Yu J, Zhang H, Li Y. RANKL inhibition: a new target of treating diabetes mellitus? Ther Adv Endocrinol Metab 2023; 14:20420188231170754. [PMID: 37223831 PMCID: PMC10201162 DOI: 10.1177/20420188231170754] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 04/03/2023] [Indexed: 05/25/2023] Open
Abstract
Accumulating evidence demonstrates the link between glucose and bone metabolism. The receptor activator of nuclear factor-kB ligand (RANKL)/the receptor activator of NF-κB (RANK)/osteoprotegerin (OPG) axis is an essential signaling axis maintaining the balance between bone resorption and bone formation. In recent years, it has been found that RANKL and RANK are distributed not only in bone but also in the liver, muscle, adipose tissue, pancreas, and other tissues that may influence glucose metabolism. Some scholars have suggested that the blockage of the RANKL signaling may protect islet β-cell function and prevent diabetes; simultaneously, there also exist different views that RANKL can improve insulin resistance through inducing the beige adipocyte differentiation and increase energy expenditure. Currently, the results of the regulatory effect on glucose metabolism of RANKL remain conflicting. Denosumab (Dmab), a fully human monoclonal antibody that can bind to RANKL and prevent osteoclast formation, is a commonly used antiosteoporosis drug. Recent basic studies have found that Dmab seems to regulate glucose homeostasis and β-cell function in humanized mice or in vitro human β-cell models. Besides, some clinical data have also reported the glucometabolic effects of Dmab, however, with limited and inconsistent results. This review mainly describes the impact of the RANKL signaling pathway on glucose metabolism and summarizes clinical evidence that links Dmab and DM to seek a new therapeutic strategy for diabetes.
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Affiliation(s)
- Baodi Xing
- Department of Endocrinology, Key Laboratory of
Endocrinology of National Health Commission, Translation Medicine Center,
Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
and Peking Union Medical College, Beijing, China
| | - Jie Yu
- Department of Endocrinology, Key Laboratory of
Endocrinology of National Health Commission, Translation Medicine Center,
Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
and Peking Union Medical College, Beijing, China
| | - Huabing Zhang
- Department of Endocrinology, NHC Key Laboratory
of Endocrinology, Peking Union Medical College Hospital (Dongdan campus),
Chinese Academy of Medical Sciences and Peking Union Medical College, No.1
Shuaifuyuan, Wangfujing Dongcheng District, Beijing 100730, China
| | - Yuxiu Li
- Department of Endocrinology, NHC Key Laboratory
of Endocrinology, Peking Union Medical College Hospital (Dongdan campus),
Chinese Academy of Medical Sciences and Peking Union Medical College, No.1
Shuaifuyuan, Wangfujing Dongcheng District, Beijing 100730, China
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25
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Dalsgaard NB, Gasbjerg LS, Helsted MM, Hansen LS, Hansen NL, Skov-Jeppesen K, Hartmann B, Holst JJ, Vilsbøll T, Knop FK. Acarbose diminishes postprandial suppression of bone resorption in patients with type 2 diabetes. Bone 2023; 170:116687. [PMID: 36754130 DOI: 10.1016/j.bone.2023.116687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 01/16/2023] [Accepted: 01/27/2023] [Indexed: 02/08/2023]
Abstract
AIMS The alpha-glucosidase inhibitor acarbose is an antidiabetic drug delaying assimilation of carbohydrates and, thus, increasing the amount of carbohydrates in the distal parts of the intestines, which in turn increases circulating levels of the gut-derived incretin hormone glucagon-like peptide 1 (GLP-1). As GLP-1 may suppress bone resorption, acarbose has been proposed to potentiate meal-induced suppression of bone resorption. We investigated the effect of acarbose treatment on postprandial bone resorption in patients with type 2 diabetes and used the GLP-1 receptor antagonist exendin(9-39)NH2 to disclose contributory effect of acarbose-induced GLP-1 secretion. METHODS In a randomised, placebo-controlled, double-blind, crossover study, 15 participants with metformin-treated type 2 diabetes (2 women/13 men, age 71 (57-85 years), BMI 29.7 (23.6-34.6 kg/m2), HbA1c 48 (40-74 mmol/mol)/6.5 (5.8-11.6 %) (median and range)) were subjected to two 14-day treatment periods with acarbose and placebo, respectively, separated by a six-week wash-out period. At the end of each period, circulating bone formation and resorption markers were assessed during two randomised 4-h liquid mixed meal tests (MMT) with infusions of exendin(9-39)NH2 and saline, respectively. Glucagon-like peptide 2 (GLP-2) was also assessed. RESULTS Compared to placebo, acarbose impaired the MMT-induced suppression of CTX as assessed by baseline-subtracted area under curve (P = 0.0037) and nadir of CTX (P = 0.0128). During acarbose treatment, exendin(9-39)NH2 infusion lowered nadir of CTX compared to saline (P = 0.0344). Neither parathyroid hormone or the bone formation marker procollagen 1 intact N-terminal propeptide were affected by acarbose or GLP-1 receptor antagonism. Acarbose treatment induced a greater postprandial GLP-2 response than placebo treatment (P = 0.0479) and exendin(9-39)NH2 infusion exacerbated this (P = 0.0002). CONCLUSIONS In patients with type 2 diabetes, treatment with acarbose reduced postprandial suppression of bone resorption. Acarbose-induced GLP-1 secretion may contribute to this phenomenon as the impairment was partially reversed by GLP-1 receptor antagonism. Also, acarbose-induced reductions in other factors reducing bone resorption, e.g. glucose-dependent insulinotropic polypeptide, may contribute.
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Affiliation(s)
- Niels B Dalsgaard
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mads M Helsted
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Laura S Hansen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Nina L Hansen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Kirsa Skov-Jeppesen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark.
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26
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Xu K, Zhang L, Yu N, Ren Z, Wang T, Zhang Y, Zhao X, Yu T. Effects of advanced glycation end products (AGEs) on the differentiation potential of primary stem cells: a systematic review. Stem Cell Res Ther 2023; 14:74. [PMID: 37038234 PMCID: PMC10088298 DOI: 10.1186/s13287-023-03324-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 03/27/2023] [Indexed: 04/12/2023] Open
Abstract
The formation and accumulation of advanced glycation end products (AGEs) have been associated with aging and the development, or worsening, of many degenerative diseases, such as atherosclerosis, chronic kidney disease, and diabetes. AGEs can accumulate in a variety of cells and tissues, and organs in the body, which in turn induces oxidative stress and inflammatory responses and adversely affects human health. In addition, under abnormal pathological conditions, AGEs create conditions that are not conducive to stem cell differentiation. Moreover, an accumulation of AGEs can affect the differentiation of stem cells. This, in turn, leads to impaired tissue repair and further aggravation of diabetic complications. Therefore, this systematic review clearly outlines the effects of AGEs on cell differentiation of various types of primary isolated stem cells and summarizes the possible regulatory mechanisms and interventions. Our study is expected to reveal the mechanism of tissue damage caused by the diabetic microenvironment from a cellular and molecular point of view and provide new ideas for treating complications caused by diabetes.
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Affiliation(s)
- Kuishuai Xu
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Liang Zhang
- Department of Abdominal Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Ning Yu
- Department of Abdominal Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Zhongkai Ren
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Tianrui Wang
- Department of Traumatology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Yingze Zhang
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Xia Zhao
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
| | - Tengbo Yu
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
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27
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Liu H, Tian F, Hu Y, Ping S, Zhang L. Liraglutide in Combination with Insulin Has a Superior Therapeutic Effect to Either Alone on Fracture Healing in Diabetic Rats. Diabetes Metab Syndr Obes 2023; 16:1235-1245. [PMID: 37151908 PMCID: PMC10155808 DOI: 10.2147/dmso.s404392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 04/10/2023] [Indexed: 05/09/2023] Open
Abstract
Purpose Fractures in patients with type 2 diabetes mellitus are at a high risk of delayed union or non-union. Previous studies have shown a protective effect of liraglutide on bone. In the present study, we aimed to investigate the effects of a combination of liraglutide and insulin on fracture healing in a rat model of diabetes and the mechanisms involved. Materials and Methods Closed femoral mid-shaft fractures were established in male Sprague-Dawley rats with or without diabetes mellitus, and the diabetic rats were administered insulin and/or liraglutide. Six weeks after femoral fracture, the femoral callus was evaluated by immunohistochemistry, histology, and micro-computed tomography. Additionally, the effects of liraglutide on high-glucose-stimulated MC3T3-E1 cells were analyzed by Western blotting. Results Micro-computed tomography and safranin O/fast green staining showed that fracture healing was delayed in the diabetic rats, and this was accompanied by much lower expression of osteogenic markers and greater osteoclast activity. However, treatment with insulin and/or liraglutide prevented these changes. Liraglutide in combination with insulin treatment resulted in lower blood glucose concentrations and significantly higher osteocalcin (OCN) and collagen I (Col I) expression six weeks following fracture. Western blot analysis showed that liraglutide prevented the low expression of the bone morphogenetic protein-2, osterix/SP7, OCN, Col I, and β-catenin in high-glucose-stimulated MC3T3-E1 cells. Conclusion These results demonstrate that insulin and/or liraglutide promotes bone fracture healing in the DF model. The combination was more effective than either single treatment, which may be because of the two drugs' additive effects on the osteogenic ability of osteoblast precursors.
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Affiliation(s)
- Hao Liu
- Department of Orthopedic Surgery, Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China
- Department of Orthopedic Syrgery, The Affiliated Hospital, North China University of Science and Technology, Tangshan, Hebei, People's Republic of China
| | - Faming Tian
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei, People’s Republic of China
| | - Yunpeng Hu
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei, People’s Republic of China
| | - Shaohua Ping
- Department of Orthopedic Syrgery, The Affiliated Hospital, North China University of Science and Technology, Tangshan, Hebei, People's Republic of China
| | - Liu Zhang
- Department of Orthopedic Surgery, Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China
- Department of Orthopedic Surgery, Emergency Management General Hospital, Beijing, People’s Republic of China
- Correspondence: Liu Zhang, Department of Orthopedic Surgery, Emergency Management General Hospital, Xibahenanli 29, Chaoyang dis, Beijing, 100028, People’s Republic of China, Tel +86-10-64662308, Email
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Wang M, Liu M, Zheng J, Xiong L, Wang P. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment. Open Med (Wars) 2023; 18:20230692. [PMID: 37034502 PMCID: PMC10080709 DOI: 10.1515/med-2023-0692] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 03/01/2023] [Accepted: 03/14/2023] [Indexed: 04/11/2023] Open
Abstract
Diabetes mellitus (DM) increases the destruction of periodontal tissue and impairs osteogenesis differentiation. Exendin-4 (Ex-4), a glucagon-like peptide-1 (GLP-1) analogue, can be used for treating DM and promotes bone regeneration. The aim of this study was to explore the effect and mechanism of Ex-4 on improving the osteogenesis of periodontal ligament stem cells (PDLSCs) in a high glucose environment. Alkaline phosphatase staining and alizarin red staining were used to detect the osteogenic differentiation of PDLSCs. The results showed that 10 nM Ex-4 could reduce the osteogenesis inhibition of PDLSCs induced by high glucose. RT-PCR and western blot results showed that Ex-4 increased the osteogenesis-related gene expression of ALP, Runx2, and Osx, and upregulated the phosphorylation of P38, JNK, and ERK1/2; the peak effect was observed in the range 0.5-1.0 h. Mitogen-activated protein kinase (MAPK) inhibitors PD98059, SB203580, and SP600125 blocked the effects of Ex-4 on MAPK activation and decreased the expression of ALP, Runx2, and Osx in PDLSCs. Moreover, after Ex-4 treatment, the total β-catenin, p-GSK3β, LEF, and Runx2 protein levels increased under normal or high glucose environments. In conclusion, our results indicated that Ex-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of PDLSCs in a high glucose environment.
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Affiliation(s)
- Min Wang
- Department of Stomatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Min Liu
- Department of Stomatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Jiawen Zheng
- Department of Stomatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Li Xiong
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ping Wang
- Department of Stomatology, The First Affiliated Hospital of Chongqing Medical University, Youyi
Road 1, Chongqing, 400016, China
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Tsai WH, Kong SK, Lin CL, Cheng KH, Cheng YT, Chien MN, Lee CC, Tsai MC. Risk of fracture caused by anti-diabetic drugs in individuals with type 2 diabetes: A network meta-analysis. Diabetes Res Clin Pract 2022; 192:110082. [PMID: 36122867 DOI: 10.1016/j.diabres.2022.110082] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 08/28/2022] [Accepted: 09/10/2022] [Indexed: 11/23/2022]
Abstract
AIMS Diabetes is associated with increased risk of fracture. This study aims to evaluate the correlation between anti-diabetic agents and fracture risk in patients with type 2 diabetes. METHODS Literature research was conducted using PubMed, Embase, and ClinicalTrials.gov. Search-term included "type 2 diabetes," "fracture," "randomized controlled trial," and seven kinds of anti-diabetic agents. Random-effect models established fractures in the follow-up period as the primary outcome. A network meta-analysis was performed to compare available treatments within a single Bayesian analytical framework. RESULTS A total of 191,361 patients were included in 161 studies, with 2916 fractures. DPP-4i (risk ratio [RR] 1.76 [95 % confidence interval (CI) 1.21-2.55]), SGLT-2i (RR 1.5 [95 % CI 1.05-2.16]) and placebo (RR 1.44 [95 % CI 1.04-1.98]) increased fracture risk when compared to GLP1-RA. GLP1-RA (RR 0.5 [95 % CI 0.31-0.79]) and SU (RR 0.56 [95 % CI 0.41-0.77]) provided greater protection against fracture than TZD. DPP-4i increased fracture risk when compared to SU (RR 1.55 [95 % CI 1.08-2.22]), and was comparable in effect to TZD. CONCLUSIONS GLP1-RA offered better protection against fracture than placebo. Insulin and SU had effects comparable with GLP1-RA. SU offered greater protection against fractures than TZD and DPP-4i. SGLT-2i increased risk of fracture when compared to GLP1-RA.
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Affiliation(s)
- Wen-Hsuan Tsai
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC
| | - Siang-Ke Kong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC
| | - Chu-Lin Lin
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Kai-Hsuan Cheng
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Yi-Ting Cheng
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Ming-Nan Chien
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC; Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Chun-Chuan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC; Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Ming-Chieh Tsai
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC; Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC; Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan, ROC.
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Habib SA, Kamal MM, El-Maraghy SA, Senousy MA. Exendin-4 enhances osteogenic differentiation of adipose tissue mesenchymal stem cells through the receptor activator of nuclear factor-kappa B and osteoprotegerin signaling pathway. J Cell Biochem 2022; 123:906-920. [PMID: 35338509 DOI: 10.1002/jcb.30236] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 02/26/2022] [Accepted: 03/03/2022] [Indexed: 12/11/2022]
Abstract
The capability of mesenchymal stem cells (MSCs) to repair bone damage and defects has long been investigated. The receptor activator of nuclear factor-kappa B (RANK), its ligand (RANKL) and the decoy receptor osteoprotegerin (OPG) axis is crucial to keep the equilibrium between osteoblastic and osteoclastic activity. Exendin-4 utilization increased bone formation and enhanced bone integrity. This study aimed to investigate the mentioned axis and determine the effect of exendin-4 upon adipose mesenchymal stem cells (Ad-MSCs) osteogenic differentiation. Ad-MSCs were isolated from rat epididymal fat, followed by characterization and then differentiation into osteocytes both in the presence or absence of exendin-4. Osteogenic differentiation was evaluated by alizarin red staining and the expression of osteogenic markers; using reverse transcriptase-quantitative polymerase chain reaction, western blotting and enzyme-linked immunoassay. MSCs derived from rat epididymal fat were isolated and characterized, along with their differentiation into osteocytes. The differentiated cells were alizarin red-stained, showing increased staining intensity upon addition of exendin-4. Moreover, the addition of exendin-4 elevated the messenger RNA expression levels of osteogenic markers; runt-related transcription factor-2 (RUNX-2), osteocalcin, and forkhead box protein O-1 while reducing the expression of the adipogenic marker peroxisome-proliferator-activated receptor-gamma. Exendin-4 addition elevated OPG levels in the supernatant of osteogenic differentiated cells. Moreover, exendin-4 elevated the protein levels of glucagon-like peptide-1 receptor and RUNX-2, while decreasing both RANK and RANKL. In conclusion, osteogenic differentiation of Ad-MSCs is associated with increased osteoblastic rather than osteoclastic activity. The findings of this study suggest that exendin-4 can enhance Ad-MSCs osteogenic differentiation partially through the RANK/RANKL/OPG axis.
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Affiliation(s)
- Sarah A Habib
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt
| | - Mohamed M Kamal
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt.,Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.,Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt
| | - Shohda A El-Maraghy
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Mahmoud A Senousy
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Shi S, Song S, Liu X, Zhao G, Ding F, Zhao W, Zhang S, Song Y, Ma W. Construction and performance of exendin-4-loaded chitosan-PLGA microspheres for enhancing implant osseointegration in type 2 diabetic rats. Drug Deliv 2022; 29:548-560. [PMID: 35156499 PMCID: PMC8856071 DOI: 10.1080/10717544.2022.2036873] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The updating and optimization of drug delivery systems is critical for better in vivo behaviors of drugs, as well as for improving impaired implant osseointegration in diabetes. Numerous studies have reported the benefits of exendin-4 on diabetic bone, with the potential to enhance osseointegration in diabetes. To construct an appropriate sustained-release system of exendin-4 targeting implant osseointegration in diabetes, this study fabricated exendin-4-loaded microspheres using poly(lactic-co-glycolic acid) (PLGA) and chitosan. The morphology, size, encapsulation efficiency, and drug release behavior of microspheres were investigated. The bioactivity of drug-loaded microspheres on cell proliferation and osteogenic differentiation of diabetic BMSCs was investigated to examine the pharmacologic action of exendin-4 loaded into chitosan-PLGA microspheres. Further, the influence of microspheres on osseointegration was evaluated using type 2 diabetes mellitus (T2DM) rat implant model. After 4 weeks, the samples were evaluated by radiological and histological analysis. The results of in vitro experiments showed that the prepared exendin-4-loaded chitosan-PLGA microspheres have good properties as a drug delivery system, and the chitosan could improve the encapsulation efficiency and drug release of PLGA microspheres. In addition, exendin-4-loaded microspheres could enhance the proliferation and osteogenic differentiation of diabetic BMSCs. The results of in vivo experiments showed the exendin-4-loaded microspheres significantly improved the impaired osseointegration and bone formation around implants in T2DM rats without affecting blood glucose levels. Thus, the local application of exendin-4-loaded chitosan-PLGA microspheres might be a promising therapeutic strategy for improving the efficacy of dental implants in T2DM individuals.
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Affiliation(s)
- Shaojie Shi
- Department of Oral Implants, School of Stomatology, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, The Fourth Military Medical University, Xi'an, China.,Department of Oral Surgery, 920th Hospital of Joint Logistics Support Force, Kunming, China
| | - Shuang Song
- Department of Implant Dentistry, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Xiangdong Liu
- Department of Oral Implants, School of Stomatology, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, The Fourth Military Medical University, Xi'an, China
| | - Guoqiang Zhao
- Department of Oral Implants, School of Stomatology, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, The Fourth Military Medical University, Xi'an, China
| | - Feng Ding
- Department of Oral Implants, School of Stomatology, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, The Fourth Military Medical University, Xi'an, China
| | - Wenshuang Zhao
- Department of Oral Implants, School of Stomatology, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, The Fourth Military Medical University, Xi'an, China
| | - Sijia Zhang
- Department of Oral Implants, School of Stomatology, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, The Fourth Military Medical University, Xi'an, China
| | - Yingliang Song
- Department of Oral Implants, School of Stomatology, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, The Fourth Military Medical University, Xi'an, China
| | - Wei Ma
- Department of Oral Implants, School of Stomatology, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, The Fourth Military Medical University, Xi'an, China
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Zhang L, He J, Sun X, Pang D, Hu J, Feng B. GIPR rs10423928 and bone mineral density in postmenopausal women in Shanghai. Endocr Connect 2022; 11:e210583. [PMID: 35029542 PMCID: PMC8859963 DOI: 10.1530/ec-21-0583] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/14/2022] [Indexed: 11/08/2022]
Abstract
We demonstrated previously that there is a correlation between glucagon-like peptide-1 (GLP-1) single-nucleotide polymorphism (SNP) and bone mineral density in postmenopausal women. Both GLP-1 and glucose-dependent insulinotropic peptide are incretins. The glucose-dependent insulinotropic peptide receptor (GIPR) SNP rs10423928 has been extensively studied. However, it is not clear whether GIPR gene mutations affect bone metabolism. The aim of this study was to investigate the association between rs10423928 and bone mineral density in postmenopausal women in Shanghai. rs10423928 was detected in 884 postmenopausal women in Shanghai, and the correlation between the GIPR SNP and bone mineral density was assessed. The dominant T/T genotype of rs10423928 was found to be related to the bone mineral density of the femoral neck (P = 0.035). Overall, our findings indicate that the dominant T/T genotype of rs10423928 in postmenopausal women is significantly associated with a higher bone mineral density and that the T/T genotype exerts a bone-protective effect.
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Affiliation(s)
- Lizhi Zhang
- Department of Endocrinology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Endocrinology, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinwei He
- Department of Osteoporosis and Bone Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Xiang Sun
- Shanghai Institute of Technology, Shanghai, China
| | - Dongyue Pang
- Department of Endocrinology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jingjing Hu
- Department of Endocrinology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bo Feng
- Department of Endocrinology, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Correspondence should be addressed to B Feng:
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The Impact of GLP1 Agonists on Bone Metabolism: A Systematic Review. Medicina (B Aires) 2022; 58:medicina58020224. [PMID: 35208548 PMCID: PMC8878541 DOI: 10.3390/medicina58020224] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/24/2022] [Accepted: 01/28/2022] [Indexed: 11/17/2022] Open
Abstract
Background and Objectives: The association between diabetes mellitus and increased risk of bone fractures has led to the investigation of the impact of antidiabetic drugs on bone metabolism. Glucagon-like peptide-1 receptor agonists (GLP1RAs) are a relatively novel and promising class of anti-hyperglycemic drugs. In addition to their blood glucose lowering action, GLP1RAs seem to have additional pleiotropic properties such as a beneficial skeletal effect; although the underlying mechanisms are not completely understood. The present systematic review summarizes current evidence about GLP1RAs and their effects on bone metabolism and fracture. Methods: An extensive literature search was conducted based on electronic databases namely, PubMed, Google Scholar and Cochrane Central Register of Controlled Trials (CENTRAL) through October 2019 to January 2020 for articles related to bone mineral density, diabetes mellitus and GLP1RAs. We included articles published in English. Finally, we included four randomized controlled trials, three meta-analyses, a case-control study and a population-based cohort analysis. Results: Based on the articles included, the animal studies indicated the salutary skeletal effects of GLP1RAs in opposition to what has been commonly observed in human studies, showing that these agents have no impact on bone mineral density (BMD) and the turnover markers. Moreover, it was demonstrated that GLP1 was not associated with fracture risk as compared to other anti-hyperglycemic drugs. Conclusions: Findings from this systematic review have demonstrated the neutral impact of GLP1RAs on BMD. Moreover, further double-blind randomized controlled trials are needed to draw more meaningful and significant conclusions on the efficacy of GLP1RAs on BMD.
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Yang Q, Fu B, Luo D, Wang H, Cao H, Chen X, Tian L, Yu X. The Multiple Biological Functions of Dipeptidyl Peptidase-4 in Bone Metabolism. Front Endocrinol (Lausanne) 2022; 13:856954. [PMID: 35586625 PMCID: PMC9109619 DOI: 10.3389/fendo.2022.856954] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 03/24/2022] [Indexed: 02/05/2023] Open
Abstract
Dipeptidyl peptidase-4 (DPP4) is a ubiquitously occurring protease involved in various physiological and pathological processes ranging from glucose homeostasis, immunoregulation, inflammation to tumorigenesis. Recently, the benefits of DPP4 inhibitors as novel hypoglycemic agents on bone metabolism have attracted extensive attraction in many studies, indicating that DPP4 inhibitors may regulate bone homeostasis. The effects of DPP4 on bone metabolism are still unclear. This paper thoroughly reviews the potential mechanisms of DPP4 for interaction with adipokines, bone cells, bone immune cells, and cytokines in skeleton system. This literature review shows that the increased DPP4 activity may indirectly promote bone resorption and inhibit bone formation, increasing the risk of osteoporosis. Thus, bone metabolic balance can be improved by decreasing DPP4 activities. The substantial evidence collected and analyzed in this review supports this implication.
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Affiliation(s)
- Qiu Yang
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
- Department of Endocrinology and Metabolism, Chengdu Fifth People’s Hospital, Chengdu, China
| | - Bing Fu
- Department of Medical Imaging, Chengdu Fifth People’s Hospital, Chengdu, China
| | - Dan Luo
- Department of General Surgery, Chengdu Fifth People’s Hospital, Chengdu, China
| | - Haibo Wang
- Department of General Surgery, Chengdu Fifth People’s Hospital, Chengdu, China
| | - Hongyi Cao
- Department of Endocrinology and Metabolism, Chengdu Fifth People’s Hospital, Chengdu, China
| | - Xiang Chen
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Li Tian
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Xijie Yu
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Xijie Yu,
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Chen Y, Zhou Y, Lin J, Zhang S. Challenges to Improve Bone Healing Under Diabetic Conditions. Front Endocrinol (Lausanne) 2022; 13:861878. [PMID: 35418946 PMCID: PMC8996179 DOI: 10.3389/fendo.2022.861878] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/02/2022] [Indexed: 12/17/2022] Open
Abstract
Diabetes mellitus (DM) can affect bone metabolism and the bone microenvironment, resulting in impaired bone healing. The mechanisms include oxidative stress, inflammation, the production of advanced glycation end products (AGEs), etc. Improving bone healing in diabetic patients has important clinical significance in promoting fracture healing and improving bone integration. In this paper, we reviewed the methods of improving bone healing under diabetic conditions, including drug therapy, biochemical cues, hyperbaric oxygen, ultrasound, laser and pulsed electromagnetic fields, although most studies are in preclinical stages. Meanwhile, we also pointed out some shortcomings and challenges, hoping to provide a potential therapeutic strategy for accelerating bone healing in patients with diabetes.
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Affiliation(s)
- Yiling Chen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yue Zhou
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jie Lin
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- *Correspondence: Jie Lin, ; Shiwen Zhang,
| | - Shiwen Zhang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- *Correspondence: Jie Lin, ; Shiwen Zhang,
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Cignarelli A, Genchi VA, Le Grazie G, Caruso I, Marrano N, Biondi G, D’Oria R, Sorice GP, Natalicchio A, Perrini S, Laviola L, Giorgino F. Mini Review: Effect of GLP-1 Receptor Agonists and SGLT-2 Inhibitors on the Growth Hormone/IGF Axis. Front Endocrinol (Lausanne) 2022; 13:846903. [PMID: 35265043 PMCID: PMC8899086 DOI: 10.3389/fendo.2022.846903] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 02/01/2022] [Indexed: 11/13/2022] Open
Abstract
Accumulating evidence supports the early use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose transporter-2 inhibitors (SGLT-2is) for the treatment of type 2 diabetes. Indeed, these compounds exert numerous pleiotropic actions that favorably affect metabolism and diabetes comorbidities, showing an additional effect beyond glucose control. Although a substantial amount of knowledge has been generated regarding the mechanism of action of both drug classes, much remains to be understood. Growth hormone (GH) is an important driver for multiple endocrine responses involving changes in glucose and lipid metabolism, and affects several tissues and organs (e.g., bone, heart). It acts directly on several target tissues, including skeletal muscle and bone, but several effects are mediated indirectly by circulating (liver-derived) or locally produced IGF-1. In consideration of the multiple metabolic and cardiovascular effects seen in subjects treated with GLP-1RAs and SGLT-2is (e.g., reduction of hyperglycemia, weight loss, free/fat mass and bone remodeling, anti-atherosclerosis, natriuresis), it is reasonable to speculate that GH and IGF-1 may play a about a relevant role in this context. This narrative mini-review aims to describe the involvement of the GH/IGF-1/IGF-1R axis in either mediating or responding to the effects of each of the two drug classes.
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Katra B, Fedak D, Matejko B, Małecki MT, Wędrychowicz A. The enteroendocrine-osseous axis in patients with long-term type 1 diabetes mellitus. Bone 2021; 153:116105. [PMID: 34245933 DOI: 10.1016/j.bone.2021.116105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/22/2021] [Accepted: 06/29/2021] [Indexed: 11/16/2022]
Abstract
INTRODUCTION The relationship between the gut and skeleton is increasingly recognized as a component of the regulation of carbohydrate metabolism. The aim of our study was to assess the relationship between bone mineral density (BMD), incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), intestinotrophic peptide glucagon-like peptide-2 (GLP-2) and osteocalcin isoforms in patients with long-term type 1 diabetes (T1D) when compared to healthy controls. METHODS Eighty two patients with long term T1D, treated in the Department of Metabolic Diseases and 53 healthy controls were recruited to the study. Long term disease duration was defined as lasting for more than 10 years. The control group was selected among age- and sex-matched healthy people. Fasting blood samples were collected to measure levels of incretin hormones (GLP-1, GLP-2, GIP), two forms of osteocalcin (uncarboxylated (ucOC), and carboxylated (cOC)), and additional biochemical parameters associated with glucose and bone metabolism (HbA1c, calcium, phosphorus, 25(OH)D3, PTH). RESULTS Patients with T1D had higher BMI than in controls (p = 0.02). There was no difference in BMD at the lumbar spine and the femoral neck between patients with long-term T1D and healthy ones. Z-score values in both groups were within normal ranges. The level of GIP was significantly higher in T1D patients (p = 0.0002) in comparison to the healthy ones. The levels of GLP-1 and GLP-2 did not differ between T1D patients and controls. In the T1D group, strong, positive associations were found between serum levels of GLP-1 and cOC (r = 0.546, p < 0.001) and between GLP-1 and total OC (r = 0.51, p < 0.001), also after adjusting for BMI (p < 0.001 and p < 0.001, respectively). Significant positive associations were also found between serum levels of GLP-2 and cOC (r = 0.27, p = 0.013) and between GLP-2 and total OC (r = 0.25, p = 0.018), also in a multivariate regression (p = 0.009, p = 0,175, respectively). Moreover, in T1D patients, GLP-1 correlated positively with the femoral neck BMD (g/cm2) (r = 0.265, p = 0.016) and this association was statistically significant after adjusting for BMI (p = 0.011). These correlations were not present in the control group. The only significant correlation observed in the control group was between OC and BMD of the neck (p = 0.049 for neck BMD g/cm2, and p = 0.041 for neck Z-score). CONCLUSIONS Our data suggests an effect of gut hormones on bone in long-term T1D, which could be associated with OC activity, however we did not find a direct connection with glucose metabolism. GLP-1 could have a possible, protective role on bone mineral density in patients with T1D. The data from our study suggests that gut hormones could be considered as a new link in the skeleton - pancreatic endocrine loop in patients with T1D.
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Affiliation(s)
- Barbara Katra
- Department of Metabolic Diseases, Jagiellonian University Medical College, Kraków, Poland
| | - Danuta Fedak
- Department of Diagnostics, Jagiellonian University Medical College, Kraków, Poland
| | - Bartłomiej Matejko
- Department of Metabolic Diseases, Jagiellonian University Medical College, Kraków, Poland
| | - Maciej T Małecki
- Department of Metabolic Diseases, Jagiellonian University Medical College, Kraków, Poland
| | - Anna Wędrychowicz
- Department of Pediatric and Adolescent Endocrinology, Pediatric Institute, Jagiellonian University Medical College, Kraków, Poland.
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Zhou Y, Xue X, Guo Y, Liu H, Hou Z, Chen Z, Wang N, Li F, Wang Y. A quinoxaline-based compound ameliorates bone loss in ovariectomized mice. Exp Biol Med (Maywood) 2021; 246:2502-2510. [PMID: 34308655 DOI: 10.1177/15353702211032133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
DMB (6,7-dichloro-2-methylsulfonyl-3-Ntert-butylaminoquinoxaline) is a quinoxaline-based compound that has been investigated as a glucagon-like peptide-1 receptor (GLP-1R) agonist. To clarify anti-osteoporosis effect of DMB, an osteoporotic mice model was established by ovariectomy (OVX) operation. The OVX mice were given intraperitoneally DMB, exendin-4 (EX-4), or 17β-estradiol (E2) for two months. Then bone mass and structure, and bone morphometric parameters were examined by micro-CT. Weight gain and food consumption, bone turnover markers, and biomechanical strength of the femur were tested, and bone histomorphometry was analyzed. The food intake and weight gain was obviously reduced by E2 or EX-4, but not DMB. However, DMB or EX-4 treatment obviously inhibited skeletal deterioration and enhanced bone strength. The improvement involved in the increased osteoblast number and level of bone formation markers, and reduced osteoclasts number and level of bone resorption markers. In addition, DMB was found to stimulate osteoblastogenesis-related marker gene expression. These results demonstrated that DMB ameliorated bone loss mainly via induction of bone formation, which suggests that the small molecule compound might be applied to the management of postmenopausal osteoporosis.
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Affiliation(s)
- Ying Zhou
- Department of Basic Medicine, Xi'an Medical University, Xi'an 710021, PR China.,Science and Technology Innovation Platform of Shaanxi Provincial Research Center for Project of Prevention and Treatment of Respiratory Diseases, Xi'an Medical University, Xi'an 710021, PR China
| | - Xiaoyan Xue
- Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi'an 710032, PR China
| | - Yanyan Guo
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, the Fourth Military Medical University, Xi'an 710038, PR China
| | - Huan Liu
- Department of Basic Medicine, Xi'an Medical University, Xi'an 710021, PR China
| | - Zheng Hou
- Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi'an 710032, PR China
| | - Zhou Chen
- Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi'an 710032, PR China
| | - Ning Wang
- Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi'an 710032, PR China
| | - Fen Li
- Department of Basic Medicine, Xi'an Medical University, Xi'an 710021, PR China
| | - Yang Wang
- Department of Basic Medicine, Xi'an Medical University, Xi'an 710021, PR China
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Kitaura H, Ogawa S, Ohori F, Noguchi T, Marahleh A, Nara Y, Pramusita A, Kinjo R, Ma J, Kanou K, Mizoguchi I. Effects of Incretin-Related Diabetes Drugs on Bone Formation and Bone Resorption. Int J Mol Sci 2021; 22:ijms22126578. [PMID: 34205264 PMCID: PMC8234693 DOI: 10.3390/ijms22126578] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Patients with type 2 diabetes have an increased risk of fracture compared to the general population. Glucose absorption is accelerated by incretin hormones, which induce insulin secretion from the pancreas. The level of the incretin hormone, glucagon-like peptide-1 (GLP-1), shows an immediate postprandial increase, and the circulating level of intact GLP-1 is reduced rapidly by dipeptidyl peptidase-4 (DPP-4)-mediated inactivation. Therefore, GLP-1 receptor agonists and DPP-4 inhibitors are effective in the treatment of type 2 diabetes. However, these incretin-related diabetic agents have been reported to affect bone metabolism, including bone formation and resorption. These agents enhance the expression of bone markers, and have been applied to improve bone quality and bone density. In addition, they have been reported to suppress chronic inflammation and reduce the levels of inflammatory cytokine expression. Previously, we reported that these incretin-related agents inhibited both the expression of inflammatory cytokines and inflammation-induced bone resorption. This review presents an overview of current knowledge regarding the effects of incretin-related diabetes drugs on osteoblast differentiation and bone formation as well as osteoclast differentiation and bone resorption. The mechanisms by which incretin-related diabetes drugs regulate bone formation and bone resorption are also discussed.
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Xie B, Chen S, Xu Y, Han W, Hu R, Chen M, Zhang Y, Ding S. The Impact of Glucagon-Like Peptide 1 Receptor Agonists on Bone Metabolism and Its Possible Mechanisms in Osteoporosis Treatment. Front Pharmacol 2021; 12:697442. [PMID: 34220521 PMCID: PMC8243369 DOI: 10.3389/fphar.2021.697442] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 05/31/2021] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus and osteoporosis are closely related and have complex influencing factors. The impact of anti-diabetic drugs on bone metabolism has received more and more attention. Type 2 diabetes mellitus (T2DM) would lead to bone fragility, high risk of fracture, poor bone repair and other bone-related diseases. Furthermore, hypoglycemic drugs used to treat T2DM may have notable detrimental effects on bones. Thus, the clinically therapeutic strategy for T2DM should not only effectively control the patient's glucose levels, but also minimize the complications of bone metabolism diseases. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are novel and promising drug for the treatment of T2DM. Some studies have found that GLP-1RAs may play an anti-osteoporotic effect by controlling blood sugar levels, promoting bone formation and inhibiting bone resorption. However, in clinical practice, the specific effects of GLP-1RA on fracture risk and osteoporosis have not been clearly defined and evidenced. This review summarizes the current research findings by which GLP-1RAs treatment of diabetic osteoporosis, postmenopausal osteoporosis and glucocorticoid-induced osteoporosis and describes possible mechanisms, such as GLP-1R/MAPK signaling pathway, GLP-1R/PI3K/AKT signaling pathway and Wnt/β-catenin pathway, that are associated with GLP-1RAs and osteoporosis. The specific role and related mechanisms of GLP-1RAs in the bone metabolism of patients with different types of osteoporosis need to be further explored and clarified.
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Affiliation(s)
- Baocheng Xie
- Department of Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China
| | - Shichun Chen
- Department of Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China
| | - Yongxiang Xu
- Department of Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China
| | - Weichao Han
- Department of Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China
| | - Runkai Hu
- Department of Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China
| | - Minyi Chen
- Department of Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China
| | - Yusheng Zhang
- Department of Pharmacy, The First People's Hospital of Foshan (The Affiliated Foshan Hospital of Sun Yat-Sen University), Foshan, China
| | - Shaobo Ding
- Department of Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China
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Donat A, Knapstein PR, Jiang S, Baranowsky A, Ballhause TM, Frosch KH, Keller J. Glucose Metabolism in Osteoblasts in Healthy and Pathophysiological Conditions. Int J Mol Sci 2021; 22:ijms22084120. [PMID: 33923498 PMCID: PMC8073638 DOI: 10.3390/ijms22084120] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/11/2021] [Accepted: 04/14/2021] [Indexed: 01/01/2023] Open
Abstract
Bone tissue in vertebrates is essential to performing movements, to protecting internal organs and to regulating calcium homeostasis. Moreover, bone has also been suggested to contribute to whole-body physiology as an endocrine organ, affecting male fertility; brain development and cognition; and glucose metabolism. A main determinant of bone quality is the constant remodeling carried out by osteoblasts and osteoclasts, a process consuming vast amounts of energy. In turn, clinical conditions associated with impaired glucose metabolism, including type I and type II diabetes and anorexia nervosa, are associated with impaired bone turnover. As osteoblasts are required for collagen synthesis and matrix mineralization, they represent one of the most important targets for pharmacological augmentation of bone mass. To fulfill their function, osteoblasts primarily utilize glucose through aerobic glycolysis, a process which is regulated by various molecular switches and generates adenosine triphosphate rapidly. In this regard, researchers have been investigating the complex processes of energy utilization in osteoblasts in recent years, not only to improve bone turnover in metabolic disease, but also to identify novel treatment options for primary bone diseases. This review focuses on the metabolism of glucose in osteoblasts in physiological and pathophysiological conditions.
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Marrano N, Biondi G, Borrelli A, Cignarelli A, Perrini S, Laviola L, Giorgino F, Natalicchio A. Irisin and Incretin Hormones: Similarities, Differences, and Implications in Type 2 Diabetes and Obesity. Biomolecules 2021; 11:286. [PMID: 33671882 PMCID: PMC7918991 DOI: 10.3390/biom11020286] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 02/09/2021] [Accepted: 02/12/2021] [Indexed: 12/11/2022] Open
Abstract
Incretins are gut hormones that potentiate glucose-stimulated insulin secretion (GSIS) after meals. Glucagon-like peptide-1 (GLP-1) is the most investigated incretin hormone, synthesized mainly by L cells in the lower gut tract. GLP-1 promotes β-cell function and survival and exerts beneficial effects in different organs and tissues. Irisin, a myokine released in response to a high-fat diet and exercise, enhances GSIS. Similar to GLP-1, irisin augments insulin biosynthesis and promotes accrual of β-cell functional mass. In addition, irisin and GLP-1 share comparable pleiotropic effects and activate similar intracellular pathways. The insulinotropic and extra-pancreatic effects of GLP-1 are reduced in type 2 diabetes (T2D) patients but preserved at pharmacological doses. GLP-1 receptor agonists (GLP-1RAs) are therefore among the most widely used antidiabetes drugs, also considered for their cardiovascular benefits and ability to promote weight loss. Irisin levels are lower in T2D patients, and in diabetic and/or obese animal models irisin administration improves glycemic control and promotes weight loss. Interestingly, recent evidence suggests that both GLP-1 and irisin are also synthesized within the pancreatic islets, in α- and β-cells, respectively. This review aims to describe the similarities between GLP-1 and irisin and to propose a new potential axis-involving the gut, muscle, and endocrine pancreas that controls energy homeostasis.
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Affiliation(s)
| | | | | | | | | | | | - Francesco Giorgino
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; (N.M.); (G.B.); (A.B.); (A.C.); (S.P.); (L.L.); (A.N.)
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Shen WR, Kitaura H, Qi J, Ogawa S, Ohori F, Noguchi T, Marahleh A, Nara Y, Adya P, Mizoguchi I. Local administration of high-dose diabetes medicine exendin-4 inhibits orthodontic tooth movement in mice. Angle Orthod 2021; 91:111-118. [PMID: 33289799 DOI: 10.2319/021320-103.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 06/01/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES To investigate the effects of exendin-4 on orthodontic tooth movement distance, root resorption, and expression levels of osteoclast-related cytokines in a mouse model. MATERIALS AND METHODS A 10-g NiTi coil spring was placed between the anterior alveolar bone and upper left first molar of 8-week-old male C57BL/6 mice. Twenty microliters of exendin-4 solution (containing 0.2 μg, 4 μg, or 20 μg exendin-4) or phosphate-buffered saline (PBS) were injected on the buccal side of the upper left first molar at 2-day intervals (4 mice per group). Mice were sacrificed on day 12; silicone impressions were taken to record tooth movement distance. The left maxillae of the PBS and 20 μg exendin-4 groups were also excised for histological analysis and quantitative reverse transcription polymerase chain reaction analysis. RESULTS Orthodontic tooth movement distance was smaller in the 20 μg exendin-4 group than in the PBS group (P < .01). Compared with the PBS group, the 20 μg exendin-4 group showed lower osteoclast number (P < .05), odontoclast number (P < .05), and root resorption surface percentage (P < .05). Relative to maxillae with PBS injections, maxillae with 20 μg exendin-4 injections had lower receptor activator of nuclear factor kappa-B ligand (RANKL) mRNA expression (P < .05), TNF-α mRNA expression (P < .05), and RANKL/osteoprotegerin (OPG) ratio (P < .01). There were no differences in the expression of OPG mRNA. CONCLUSIONS Exendin-4 inhibits orthodontic tooth movement. Therefore, additional attention is needed for orthodontic patients who receive exendin-4 for diabetes treatment. GLP-1 receptor may be a treatment target for patients with severe root resorption.
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Liang Q, Du L, Zhang R, Kang W, Ge S. Stromal cell-derived factor-1/Exendin-4 cotherapy facilitates the proliferation, migration and osteogenic differentiation of human periodontal ligament stem cells in vitro and promotes periodontal bone regeneration in vivo. Cell Prolif 2021; 54:e12997. [PMID: 33511708 PMCID: PMC7941242 DOI: 10.1111/cpr.12997] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 01/06/2021] [Accepted: 01/10/2021] [Indexed: 12/12/2022] Open
Abstract
Objectives Stromal cell‐derived factor‐1 (SDF‐1) actively directs endogenous cell homing. Exendin‐4 (EX‐4) promotes stem cell osteogenic differentiation. Studies revealed that EX‐4 strengthened SDF‐1‐mediated stem cell migration. However, the effects of SDF‐1 and EX‐4 on periodontal ligament stem cells (PDLSCs) and bone regeneration have not been investigated. In this study, we aimed to evaluate the effects of SDF‐1/EX‐4 cotherapy on PDLSCs in vitro and periodontal bone regeneration in vivo. Methods Cell‐counting kit‐8 (CCK8), transwell assay, qRT‐PCR and western blot were used to determine the effects and mechanism of SDF‐1/EX‐4 cotherapy on PDLSCs in vitro. A rat periodontal bone defect model was developed to evaluate the effects of topical application of SDF‐1 and systemic injection of EX‐4 on endogenous cell recruitment, osteoclastogenesis and bone regeneration in vivo. Results SDF‐1/EX‐4 cotherapy had additive effects on PDLSC proliferation, migration, alkaline phosphatase (ALP) activity, mineral deposition and osteogenesis‐related gene expression compared to SDF‐1 or EX‐4 in vitro. Pretreatment with ERK inhibitor U0126 blocked SDF‐1/EX‐4 cotherapy induced ERK signal activation and PDLSC proliferation. SDF‐1/EX‐4 cotherapy significantly promoted new bone formation, recruited more CXCR4+ cells and CD90+/CD34‐ stromal cells to the defects, enhanced early‐stage osteoclastogenesis and osteogenesis‐related markers expression in regenerated bone compared to control, SDF‐1 or EX‐4 in vivo. Conclusions SDF‐1/EX‐4 cotherapy synergistically regulated PDLSC activities, promoted periodontal bone formation, thereby providing a new strategy for periodontal bone regeneration.
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Affiliation(s)
- Qianyu Liang
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan Shandong, China
| | - Lingqian Du
- Department of Stomatology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan Shandong, China
| | - Rui Zhang
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan Shandong, China.,Department of Endodontics, Hospital of stomatology, Zunyi Medical University, Zunyi Guizhou, China
| | - Wenyan Kang
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan Shandong, China
| | - Shaohua Ge
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan Shandong, China
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Deng Y, Zhu W, Anhua Lin, Wang C, Xiong C, Xu F, Li J, Huang S, Zhang N, Huo Y. Exendin-4 promotes bone formation in diabetic states via HDAC1-Wnt/β-catenin axis. Biochem Biophys Res Commun 2021; 544:8-14. [PMID: 33516884 DOI: 10.1016/j.bbrc.2021.01.039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 01/13/2021] [Indexed: 02/08/2023]
Abstract
Exendin-4 has been found to have hypoglycemic effect and prevent bone loss in diabetic patients, but its mechanism of preventing bone loss is still unclear. In this study, high-fat diet combined with streptozotocin was used to establish type 2 diabetes mellitus (T2DM) mice, and bone marrow mesenchyme stem cells (BMSCs) were isolated for osteogenic induction in vitro. Alizarin red staining and ALP activity detection were used to observe the effect of exendin-4 on osteogenic differentiation of BMSCs. Western blot was used to detect the proteins expression in BMSCs. In vivo, the effects of exendin-4 treatment on body weight, blood glucose, bone density and bone quality of T2DM mice were observed by treatment with exendin-4. The results showed that exendin-4 promoted osteogenic differentiation of T2DM derived BMSCs, down-regulated histone deacetylase 1 (HDAC1) and p-β-Catenin proteins expression, and up-regulated Wnt3, β-Catenin and runt-related transcription factor 2 (Runx 2) proteins expression. In vivo, exendin-4 effectively suppressed the blood glucose and increased body weight of T2DM mice, and significantly improved bone density and bone quality of the right tibia. Interestingly, by over-expression of HDAC1 in BMSCs, the effect of exendin-4 on promoting osteogenic differentiation of BMSCs was attenuated, and the regulation of Wnt3a, β-Catenin, p-β-Catenin or Runx2 proteins were reversed. By injecting adenovirus containing HDAC1 into the right tibia of mice, the effect of exendin-4 on bone density and bone quality of T2DM mice was significantly attenuated. All above results suggest that the HDAC1-Wnt/β-Catenin signal axis is involved in the anti-diabetic bone loss effect of exendin-4, and HDAC1 may be the target of exendin-4.
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Affiliation(s)
- Ying Deng
- Endocrinology Department, Jiangxi Provincial People(')s Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Wenyi Zhu
- Medical Department of Graduate School, Nanchang University, Nanchang, PR China
| | - Anhua Lin
- Endocrinology Department, Jiangxi Provincial People(')s Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Chenxiu Wang
- Endocrinology Department, Jiangxi Provincial People(')s Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Changhui Xiong
- Department of Science and Education, Jiangxi Provincial People(')s Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Fanghua Xu
- Pathology Department, Pingxiang People's Hospital of Southern Medical University, Pingxiang, Jiangxi, 337055, PR China
| | - Jinfeng Li
- Endocrinology Department, Jiangxi Provincial People(')s Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Shuijin Huang
- Endocrinology Department, Jiangxi Provincial People(')s Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Na Zhang
- Endocrinology Department, Jiangxi Provincial People(')s Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Yanan Huo
- Endocrinology Department, Jiangxi Provincial People(')s Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, 330006, PR China.
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Liu W, Jing X, Xu Z, Teng C. PEGDA/HA mineralized hydrogel loaded with Exendin4 promotes bone regeneration in rat models with bone defects by inducing osteogenesis. J Biomater Appl 2021; 35:1337-1346. [PMID: 33467965 DOI: 10.1177/0885328220987046] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Scaffolds with osteogenic differentiation function play an important role in the healing process of bone defects. Here, we designed a high strength Poly(ethyleneglycol) diacrylate/Hydroxyapatite (PEGDA/HA) mineralized hydrogel loaded with Exendin4 for inducing osteogenic differentiation. In this study, PEGDA hydrogel was prepared by photo initiating method. PEGDA/HA mineralized hydrogel was prepared by in-situ precipitation method, and Exendin4 was loaded by gel adsorption. The effects of different calcium and phosphorus concentrations on the strength and Exendin4 release of PEGDA/HA hydrogels were investigated. Rat models of bone defect were made and randomly divided into 5 groups. The experimental group was implanted with PEGDA hydrogel, Exendin4-PEGDA hydrogel, PEGDA/HA mineralized hydrogel, Exendin4-PEGDA/HA mineralized hydrogel, and no materials were implanted in the blank control group. Computed tomography (CT) and histology were observed 4 and 8 weeks after operation. Our results revealed that the PEGDA/HA mineralized hydrogel had porous structure, high mechanical strength and good biocompatibility. In vitro release test showed that the mineralized hydrogel exhibited good sustained release profile within 20 d. The animal experiments showed that the mineralized hydrogel accelerated the formation of new bone after 4 and 8 weeks, and formed a seamless union on the defected bone area after 8 weeks. In conclusions, The Exendin4-PEGDA/HA mineralized hydrogel can effectively repair bone defects in rats, and it is expected to be used as a biomaterial for human bone tissue repair.
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Affiliation(s)
- Wei Liu
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, China
| | - Xiaowei Jing
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, China
| | - Zhiwen Xu
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, China
| | - Chong Teng
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, China
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Yu J, Shi YC, Ping F, Li W, Zhang HB, He SL, Zhao Y, Xu LL, Li YX. Liraglutide Inhibits Osteoclastogenesis and Improves Bone Loss by Downregulating Trem2 in Female Type 1 Diabetic Mice: Findings From Transcriptomics. Front Endocrinol (Lausanne) 2021; 12:763646. [PMID: 34975749 PMCID: PMC8715718 DOI: 10.3389/fendo.2021.763646] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 11/08/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The mechanisms of bone fragility in type 1 diabetes (T1D) are not fully understood. Whether glucagon-like peptide-1 receptor (GLP-1R) agonists could improve bone quality in T1D context also remains elusive. AIMS We aimed to explore the possible mechanisms of bone loss in T1D and clarify whether liraglutide has effects on bone quality of T1D mice using transcriptomics. METHODS Female streptozotocin-induced diabetic C57BL/6J mice were randomly divided into four groups and received the following treatments daily for 8 weeks: saline as controls, insulin, liraglutide, and liraglutide combined with insulin. These groups were also compared with non-STZ-treated normal glucose tolerance (NGT) group. Trunk blood and bone tissues were collected for analysis. Three tibia from each of the NGT, saline-treated, and liraglutide-treated groups were randomly selected for transcriptomics. RESULTS Compared with NGT mice, saline-treated T1D mice manifested markedly hyperglycemia and weight loss, and micro-CT revealed significantly lower bone mineral density (BMD) and deficient microarchitectures in tibias. Eight weeks of treatment with liraglutide alone or combined with insulin rescued the decreased BMD and partly corrected the compromised trabecular microarchitectures. Transcriptomics analysis showed there were 789 differentially expressed genes mainly mapped to osteoclastogenesis and inflammation pathways. The RT-qPCR verified that the gene expression of Trem2, Nfatc1, Trap, and Ctsk were significantly increased in the tibia of T1D compared with those in the NGT group. Liraglutide treatment alone or combined with insulin could effectively suppress osteoclastogenesis by downregulating the gene expression of Trem2, Nfatc1, Ctsk, and Trap. CONCLUSIONS Taken together, increased osteoclastogenesis with upregulated expression of Trem2 played an important role in bone loss of T1D mice. Liraglutide provided protective effects on bone loss in T1D mice by suppressing osteoclastogenesis.
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Affiliation(s)
- Jie Yu
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yan-Chuan Shi
- Group of Neuroendocrinology, Diabetes and Metabolism Division, Garvan Institute of Medical Research, St Vincent’s Hospital, Sydney, NSW, Australia
- Faculty of Medicine, UNSW, Sydney, NSW, Australia
| | - Fan Ping
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Wei Li
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hua-Bing Zhang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shu-Li He
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yuan Zhao
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ling-Ling Xu
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- *Correspondence: Ling-Ling Xu, ; Yu-Xiu Li,
| | - Yu-Xiu Li
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- *Correspondence: Ling-Ling Xu, ; Yu-Xiu Li,
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Abstract
INTRODUCTION Preclinical, clinical, and population-based studies have provided evidence that anti-diabetic drugs affect bone metabolism and may affect the risk of fracture in diabetic patients. AREAS COVERED An overview of the skeletal effects of anti-diabetic drugs used in type 2 diabetes is provided. Searches on AdisInsight, PubMed, and Medline databases were conducted up to 1st July 2020. The latest evidence from randomized clinical trials and population-based studies on the skeletal safety of the most recent drugs (DPP-4i, GLP-1RA, and SGLT-2i) is provided. EXPERT OPINION Diabetic patients present with a higher risk of fracture for a given bone mineral density suggesting a role of bone quality in the etiology of diabetic fracture. Bone quality is difficult to assess in human clinical practice and the use of preclinical models provides valuable information on diabetic bone alterations. As several links have been established between bone and energy homeostasis, it is interesting to study the safety of anti-diabetic drugs on the skeleton. So far, evidence for the newest molecules suggests a neutral fracture risk, but further studies, especially in different types of patient populations (patients at risk or with history of cardiovascular disease, renal impairment, neuropathy) are required to fully appreciate this matter.
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Affiliation(s)
- Guillaume Mabilleau
- Groupe Etude Remodelage Osseux et biomatériaux, GEROM, UPRES EA 4658, UNIV Angers, SFR ICAT 4208, Institut de Biologie en Santé , Angers, France
- Service Commun d'Imagerie et Analyses Microscopiques, SCIAM, UNIV Angers, SFR ICAT 4208, Institut de Biologie en Santé , Angers, France
- Bone pathology unit, Angers University hospital , Angers Cedex, France
| | - Béatrice Bouvard
- Groupe Etude Remodelage Osseux et biomatériaux, GEROM, UPRES EA 4658, UNIV Angers, SFR ICAT 4208, Institut de Biologie en Santé , Angers, France
- Rheumatology department, Angers University Hospital , Angers Cedex, France
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Guerrero-Pérez F, Casajoana A, Gómez-Vaquero C, Virgili N, López-Urdiales R, Hernández-Montoliu L, Pujol-Gebelli J, Osorio J, Prats A, Vidal-Alabró A, Pérez-Maraver M, Fernández-Veledo S, Vendrell J, Vilarrasa N. Long-Term Effects in Bone Mineral Density after Different Bariatric Procedures in Patients with Type 2 Diabetes: Outcomes of a Randomized Clinical Trial. J Clin Med 2020; 9:jcm9061830. [PMID: 32545353 PMCID: PMC7356739 DOI: 10.3390/jcm9061830] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/05/2020] [Accepted: 06/08/2020] [Indexed: 11/16/2022] Open
Abstract
There is scant evidence of the long-term effects of bariatric surgery on bone mineral density (BMD). We compared BMD changes in patients with severe obesity and type 2 diabetes (T2D) 5 years after randomization to metabolic gastric bypass (mRYGB), sleeve gastrectomy (SG) and greater curvature plication (GCP). We studied the influence of first year gastrointestinal hormone changes on final bone outcomes. Forty-five patients, averaging 49.4 (7.8) years old and body mass index (BMI) 39.4 (1.9) kg/m2, were included. BMD at lumbar spine (LS) was lower after mRYGB compared to SG and GCP: 0.89 [0.82;0.94] vs. 1.04 [0.91;1.16] vs. 0.99 [0.89;1.12], p = 0.020. A higher percentage of LS osteopenia was present after mRYGB 78.6% vs. 33.3% vs. 50.0%, respectively. BMD reduction was greater in T2D remitters vs. non-remitters. Weight at fifth year predicted BMD changes at the femoral neck (FN) (adjusted R2: 0.3218; p = 0.002), and type of surgery (mRYGB) and menopause predicted BMD changes at LS (adjusted R2: 0.2507; p < 0.015). In conclusion, mRYGB produces higher deleterious effects on bone at LS compared to SG and GCP in the long-term. Women in menopause undergoing mRYGB are at highest risk of bone deterioration. Gastrointestinal hormone changes after surgery do not play a major role in BMD outcomes.
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Affiliation(s)
- Fernando Guerrero-Pérez
- Department of Endocrinology and Nutrition, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain; (F.G.-P.); (N.V.); (R.L.-U.); (L.H.-M.); (M.P.-M.)
| | - Anna Casajoana
- Bariatric Surgery Unit, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain; (A.C.); (J.P.-G.); (J.O.)
| | - Carmen Gómez-Vaquero
- Department of Rheumatology, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain;
| | - Nuria Virgili
- Department of Endocrinology and Nutrition, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain; (F.G.-P.); (N.V.); (R.L.-U.); (L.H.-M.); (M.P.-M.)
| | - Rafael López-Urdiales
- Department of Endocrinology and Nutrition, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain; (F.G.-P.); (N.V.); (R.L.-U.); (L.H.-M.); (M.P.-M.)
| | - Laura Hernández-Montoliu
- Department of Endocrinology and Nutrition, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain; (F.G.-P.); (N.V.); (R.L.-U.); (L.H.-M.); (M.P.-M.)
| | - Jordi Pujol-Gebelli
- Bariatric Surgery Unit, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain; (A.C.); (J.P.-G.); (J.O.)
| | - Javier Osorio
- Bariatric Surgery Unit, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain; (A.C.); (J.P.-G.); (J.O.)
| | - Anna Prats
- Clinical Nutrition Unit, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain;
| | - Anna Vidal-Alabró
- Instituto de Investigación Biomédica-IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain;
| | - Manuel Pérez-Maraver
- Department of Endocrinology and Nutrition, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain; (F.G.-P.); (N.V.); (R.L.-U.); (L.H.-M.); (M.P.-M.)
- Instituto de Investigación Biomédica-IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain;
- CIBERDEM-CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28014 Madrid, Spain; (S.F.-V.); (J.V.)
| | - Sonia Fernández-Veledo
- CIBERDEM-CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28014 Madrid, Spain; (S.F.-V.); (J.V.)
- Pere Virgili Research Institute (IISPV), University Hospital Joan XXIII, 43005and Rovira i Virgili University, 43003 Tarragona, Spain
| | - Joan Vendrell
- CIBERDEM-CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28014 Madrid, Spain; (S.F.-V.); (J.V.)
- Pere Virgili Research Institute (IISPV), University Hospital Joan XXIII, 43005and Rovira i Virgili University, 43003 Tarragona, Spain
| | - Nuria Vilarrasa
- Department of Endocrinology and Nutrition, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain; (F.G.-P.); (N.V.); (R.L.-U.); (L.H.-M.); (M.P.-M.)
- CIBERDEM-CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28014 Madrid, Spain; (S.F.-V.); (J.V.)
- Correspondence: ; Tel.: +34-932-602-784
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50
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Zhang Y, Han B, Wei Y, Jing J, Li J. Icariin Promotes Fracture Healing in Ovariectomized Rats. Med Sci Monit 2020; 26:e924554. [PMID: 32342947 PMCID: PMC7201894 DOI: 10.12659/msm.924554] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 04/09/2020] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Osteoporotic fractures are common in postmenopausal women and associated with complications. Numerous studies have demonstrated that icariin can be used to treat fractures and osteoporosis. Herein, we evaluated the efficacy of gavage-administered icariin to promote fracture healing in postmenopausal osteoporotic fracture (POF) rats. MATERIAL AND METHODS In this study, ovariectomy-induced POF rats were treated with 600 mg/kg icariin. Micro-computed tomography (micro-CT) was used to assess fracture healing; besides, serum APK, TRACP-5b, and E₂ expression levels were detected by commercial kits, and the uterine index was calculated. In addition, the expression of osteogenesis-related proteins (Runx 2 and COL1A2) in the callus was measured by western blot, whereas the expression of OPG/RANKL pathway proteins was measured by western blot and immunohistochemical analysis. RESULTS Our data revealed that icariin promoted the expression level of Runx 2 and COL1A2 and suppressed the expression level of serum bone turn over biomarkers via the OPG/RANKL pathway. Besides, a more mature callus was observed in the POF rats receiving icariin than in the untreated POF rats, while serum E₂ and uterine index were unaffected by icariin treatment. CONCLUSIONS These results revealed that icariin could promote fracture healing in ovariectomized rats via OPG/RANKL signaling, and that serum E₂ and uterine index were not affected by icariin treatment.
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Affiliation(s)
- Yong Zhang
- Department of Orthopaedics, The Second Hospital of Anhui Medical University, Hefei, Anhui, P.R. China
| | - Bing Han
- Department of Orthopaedics, The First People’s Hospital of Anqing, Anqing, Anhui, P.R. China
| | - Yong Wei
- Department of Orthopaedics, The Second Hospital of Anhui Medical University, Hefei, Anhui, P.R. China
| | - Juehua Jing
- Department of Orthopaedics, The Second Hospital of Anhui Medical University, Hefei, Anhui, P.R. China
| | - Jun Li
- Department of Orthopaedics, The Second Hospital of Anhui Medical University, Hefei, Anhui, P.R. China
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