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Li Y, Luo Y, Huang D, Peng L. Sclerostin as a new target of diabetes-induced osteoporosis. Front Endocrinol (Lausanne) 2024; 15:1491066. [PMID: 39720253 PMCID: PMC11666367 DOI: 10.3389/fendo.2024.1491066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 11/25/2024] [Indexed: 12/26/2024] Open
Abstract
Sclerostin, a protein synthesized by bone cells, is a product of the SOST gene. Sclerostin is a potent soluble inhibitor of the WNT signaling pathway, and is known to inhibit bone formation by inhibiting osteocyte differentiation and function. Currently, sclerostin has been the subject of numerous animal experiments and clinical investigations. By conducting a literature review, we have gained insights into the most recent advancements in research. Patients with both type 1 diabetes and type 2 diabetes have high levels of serum sclerostin. Patients with type 1 diabetes and type 2 diabetes are both more likely to suffer from osteoporosis, and serum sclerostin levels are elevated in osteoporosis. Many studies have confirmed that sclerostin has been implicated in the pathogenesis of osteoporosis, so we speculate that sclerostin plays an important role in osteoporosis through the glucose metabolism pathway, which may promote the osteoporosis of morbidity in type 1 diabetes and type 2 diabetes. Based on this, we propose whether serum sclerostin can predict type 1 diabetes and type 2 diabetes-induced osteoporosis, and whether it can be a new target for the prevention and treatment of type 1 diabetes and type 2 diabetes-induced osteoporosis, providing new ideas for clinicians and researchers.
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Affiliation(s)
- Yanhua Li
- Department of Endocrinology and Metabolism, The Third Hospital of Changsha, Changsha, Hunan, China
| | - Yaheng Luo
- Department of Endocrinology and Metabolism, The Third Hospital of Changsha, Changsha, Hunan, China
| | - Debin Huang
- Department of Endocrinology and Metabolism, The Third Hospital of Changsha, Changsha, Hunan, China
| | - Lele Peng
- Department of Endocrinology and Metabolism, Want Want Hospital, Changsha, Hunan, China
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Marino S, Ozgurel SU, McAndrews K, Cregor M, Villaseñor A, Mamani-Huanca M, Barbas C, Gortazar A, Sato AY, Bellido T. Abaloparatide is more potent than teriparatide in restoring bone mass and strength in type 1 diabetic male mice. Bone 2024; 181:117042. [PMID: 38360197 DOI: 10.1016/j.bone.2024.117042] [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: 12/19/2023] [Revised: 02/02/2024] [Accepted: 02/03/2024] [Indexed: 02/17/2024]
Abstract
This study investigated the efficacy of the two FDA-approved bone anabolic ligands of the parathyroid hormone receptor 1 (PTH1R), teriparatide or human parathyroid hormone 1-34 (PTH) and abaloparatide (ABL), to restoring skeletal health using a preclinical murine model of streptozotocin-induced T1-DM. Intermittent daily subcutaneous injections of equal molar doses (12 pmoles/g/day) of PTH (50 ng/g/day), ABL (47.5 ng/g/day), or vehicle, were administered for 28 days to 5-month-old C57Bl/6 J male mice with established T1-DM or control (C) mice. ABL was superior to PTH in increasing or restoring bone mass in control or T1-MD mice, respectively, which was associated with superior stimulation of trabecular and periosteal bone formation, upregulation of osteoclastic/osteoblastic gene expression, and increased circulating bone remodeling markers. Only ABL corrected the reduction in ultimate load, which is a measure of bone strength, induced by T1-DM, and it also increased energy to ultimate load. In addition, bones from T1-DM mice treated with PTH or ABL exhibited increased ultimate stress, a material index, compared to T1-DM mice administered with vehicle. And both PTH and ABL prevented the increased expression of the Wnt antagonist Sost/sclerostin displayed by T1-DM mice. Further, PTH and ABL increased to a similar extent the circulating bone resorption marker CTX and the bone formation marker P1NP in T1-DM after 2 weeks of treatment; however, only ABL sustained these increases after 4 weeks of treatment. We conclude that at equal molar doses, ABL is more effective than PTH in increasing bone mass and restoring the cortical and trabecular bone lost with T1-DM, due to higher and longer-lasting increases in bone remodeling.
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Affiliation(s)
- Silvia Marino
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Central Arkansas Veterans Healthcare System, John L. McClellan Little Rock, AR, USA.
| | - Serra Ucer Ozgurel
- Indiana University School of Medicine, Indianapolis, IN, USA; Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
| | - Kevin McAndrews
- Indiana University School of Medicine, Indianapolis, IN, USA; Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
| | - Meloney Cregor
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Central Arkansas Veterans Healthcare System, John L. McClellan Little Rock, AR, USA; Indiana University School of Medicine, Indianapolis, IN, USA; Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
| | - Alma Villaseñor
- Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorcón, Madrid, Spain.
| | - Maricuz Mamani-Huanca
- Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorcón, Madrid, Spain.
| | - Coral Barbas
- Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorcón, Madrid, Spain.
| | - Arancha Gortazar
- Bone Physiopathology laboratory, Applied Molecular Medicine Institute (IMMA), Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorcón, Madrid, Spain.
| | - Amy Y Sato
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Central Arkansas Veterans Healthcare System, John L. McClellan Little Rock, AR, USA; Indiana University School of Medicine, Indianapolis, IN, USA; Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
| | - Teresita Bellido
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Central Arkansas Veterans Healthcare System, John L. McClellan Little Rock, AR, USA; Indiana University School of Medicine, Indianapolis, IN, USA; Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
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Liu H, Liu L, Rosen CJ. PTH and the Regulation of Mesenchymal Cells within the Bone Marrow Niche. Cells 2024; 13:406. [PMID: 38474370 PMCID: PMC10930661 DOI: 10.3390/cells13050406] [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: 12/05/2023] [Revised: 02/05/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Parathyroid hormone (PTH) plays a pivotal role in maintaining calcium homeostasis, largely by modulating bone remodeling processes. Its effects on bone are notably dependent on the duration and frequency of exposure. Specifically, PTH can initiate both bone formation and resorption, with the outcome being influenced by the manner of PTH administration: continuous or intermittent. In continuous administration, PTH tends to promote bone resorption, possibly by regulating certain genes within bone cells. Conversely, intermittent exposure generally favors bone formation, possibly through transient gene activation. PTH's role extends to various aspects of bone cell activity. It directly influences skeletal stem cells, osteoblastic lineage cells, osteocytes, and T cells, playing a critical role in bone generation. Simultaneously, it indirectly affects osteoclast precursor cells and osteoclasts, and has a direct impact on T cells, contributing to its role in bone resorption. Despite these insights, the intricate mechanisms through which PTH acts within the bone marrow niche are not entirely understood. This article reviews the dual roles of PTH-catabolic and anabolic-on bone cells, highlighting the cellular and molecular pathways involved in these processes. The complex interplay of these factors in bone remodeling underscores the need for further investigation to fully comprehend PTH's multifaceted influence on bone health.
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Affiliation(s)
- Hanghang Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China;
- Maine Medical Center, MaineHealth Institute for Research, 81 Research Drive, Scarborough, ME 04074, USA;
| | - Linyi Liu
- Maine Medical Center, MaineHealth Institute for Research, 81 Research Drive, Scarborough, ME 04074, USA;
| | - Clifford J. Rosen
- Maine Medical Center, MaineHealth Institute for Research, 81 Research Drive, Scarborough, ME 04074, USA;
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Zhang M, Gao Y, Li Q, Cao H, Yang J, Cai X, Xiao J. Downregulation of DNA methyltransferase-3a ameliorates the osteogenic differentiation ability of adipose-derived stem cells in diabetic osteoporosis via Wnt/β-catenin signaling pathway. Stem Cell Res Ther 2022; 13:397. [PMID: 35927735 PMCID: PMC9351106 DOI: 10.1186/s13287-022-03088-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 07/23/2022] [Indexed: 02/06/2023] Open
Abstract
Background Diabetes-related osteoporosis (DOP) is a chronic disease caused by the high glucose environment that induces a metabolic disorder of osteocytes and osteoblast-associated mesenchymal stem cells. The processes of bone defect repair and regeneration become extremely difficult with DOP. Adipose-derived stem cells (ASCs), as seed cells in bone tissue engineering technology, provide a promising therapeutic approach for bone regeneration in DOP patients. The osteogenic ability of ASCs is lower in a DOP model than that of control ASCs. DNA methylation, as a mechanism of epigenetic regulation, may be involved in DNA methylation of various genes, thereby participating in biological behaviors of various cells. Emerging evidence suggests that increased DNA methylation levels are associated with activation of Wnt/β-catenin signaling pathway. The purpose of this study was to investigate the influence of the diabetic environment on the osteogenic potential of ASCs, to explore the role of DNA methylation on osteogenic differentiation of DOP-ASCs via Wnt/β-catenin signaling pathway, and to improve the osteogenic differentiation ability of ASCs with DOP. Methods DOP-ASCs and control ASCs were isolated from DOP C57BL/6 and control mice, respectively. The multipotency of DOP-ASCs was confirmed by Alizarin Red-S, Oil Red-O, and Alcian blue staining. Real-time polymerase chain reaction (RT-PCR), immunofluorescence, and western blotting were used to analyze changes in markers of osteogenic differentiation, DNA methylation, and Wnt/β-catenin signaling. Alizarin Red-S staining was also used to confirm changes in the osteogenic ability. DNMT small interfering RNA (siRNA), shRNA-Dnmt3a, and LVRNA-Dnmt3a were used to assess the role of Dnmt3a in osteogenic differentiation of control ASCs and DOP-ASCs. Micro-computed tomography, hematoxylin and eosin staining, and Masson staining were used to analyze changes in the osteogenic capability while downregulating Dnmt3a with lentivirus in DOP mice in vivo. Results The proliferative ability of DOP-ASCs was lower than that of control ASCs. DOP-ASCs showed a decrease in osteogenic differentiation capacity, lower Wnt/β-catenin signaling pathway activity, and a higher level of Dnmt3a than control ASCs. When Dnmt3a was downregulated by siRNA and shRNA, osteogenic-related factors Runt-related transcription factor 2 and osteopontin, and activity of Wnt/β-catenin signaling pathway were increased, which rescued the poor osteogenic potential of DOP-ASCs. When Dnmt3a was upregulated by LVRNA-Dnmt3a, the osteogenic ability was inhibited. The same results were obtained in vivo. Conclusions Dnmt3a silencing rescues the negative effects of DOP on ASCs and provides a possible approach for bone tissue regeneration in patients with diabetic osteoporosis.
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Affiliation(s)
- Maorui Zhang
- Department of Oral Implantology, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, China.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Yujin Gao
- Department of Oral Implantology, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, China.,Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Qing Li
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Huayue Cao
- Department of Oral Implantology, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Jianghua Yang
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Xiaoxiao Cai
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Jingang Xiao
- Department of Oral Implantology, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, China. .,Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China. .,Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, China.
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Effect of chronic lithium on mechanical sensitivity and trabecular bone loss induced by type-1 diabetes mellitus in mice. Biometals 2022; 35:1033-1042. [PMID: 35849260 DOI: 10.1007/s10534-022-00421-5] [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: 05/02/2022] [Accepted: 07/04/2022] [Indexed: 11/02/2022]
Abstract
Type-1 diabetes mellitus (T1DM) is a chronic condition characterized by long-term hyperglycemia that results in several complications such as painful peripheral neuropathy, bone deterioration, and increased risk of bone fractures. Lithium, a first-line therapy for bipolar disorder, has become an attractive agent for attenuating peripheral neuropathy and menopause-induced bone loss. Therefore, our aim was to determine the effect of chronic lithium treatment on mechanical hypersensitivity and trabecular bone loss induced by T1DM in mice. T1DM was induced in male C57BL/6J mice by intraperitoneal injection of streptozotocin (STZ, 50 mg/kg/day, for 5 consecutive days). 12 weeks after T1DM-induction, mice received a daily intraperitoneal injection of vehicle, 30 or 60 mg/kg lithium (as LiCl) for 6 weeks. Throughout the treatment period, blood glucose levels and mechanical sensitivity were evaluated every 2 weeks. After lithium treatment, the femur and L5 vertebra were harvested for microcomputed tomography (microCT) analysis. T1DM mice showed significant hyperglycemia, mechanical hypersensitivity, and significant trabecular bone loss as compared with the control group. Chronic lithium treatment did not revert the hindpaw mechanical hypersensitivity nor hyperglycemia associated to T1DM induced by STZ. In contrast, microCT analysis revealed that lithium reverted, in a dose-dependent manner, the loss of trabecular bone associated to T1DM induced by STZ at both the distal femur and L5 vertebra. Lithium treatment by itself did not affect any trabecular bone parameter in non-diabetic mice.
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Ikezaki-Amada K, Miyamoto Y, Sasa K, Yamada A, Kinoshita M, Yoshimura K, Kawai R, Yano F, Shirota T, Kamijo R. Extracellular acidification augments sclerostin and osteoprotegerin production by Ocy454 mouse osteocytes. Biochem Biophys Res Commun 2022; 597:44-51. [PMID: 35123265 DOI: 10.1016/j.bbrc.2022.01.111] [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: 01/26/2022] [Accepted: 01/28/2022] [Indexed: 11/21/2022]
Abstract
Osteocytes sense the microenvironmental stimuli, including mechanical stress, and regulate bone resorption by osteoclasts and bone formation by osteoblasts. Diabetes and cancer metastasis to bone raise l-lactic acid in the bone tissue, causing acidification. Here, we investigated the effects of l-lactic acid and extracellular acidification on the function of mouse Ocy454 osteocytes. L- and d-lactic acid with low chiral selectivity and acidification of the medium raised the production of sclerostin and osteoprotegerin by Ocy454 cells. The mRNA expression of their genes increased after either treatment of L- and d-lactic acid or acidification of the medium. Furthermore, the conditioned medium of Ocy454 cells cultured in an acidic environment suppressed the induction of alkaline phosphatase activity in MC3T3-E1 cells, which was recovered by the anti-sclerostin antibody. While it is reported that HDAC5 inhibits the transcription of the sclerostin gene, extracellular acidification reduced the nuclear localization of HDAC5 in Ocy454 cells. While calmodulin kinase II (CaMKII) is known to phosphorylate and induce extranuclear translocation of HDAC5, KN-62, an inhibitor of CaMKII lowered the expression of the sclerostin gene in Ocy454 cells. Collectively, extracellular acidification is a microenvironmental factor that modulates osteocyte functions.
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Affiliation(s)
- Kaori Ikezaki-Amada
- Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan; Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Tokyo, Japan
| | - Yoichi Miyamoto
- Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan.
| | - Kiyohito Sasa
- Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan
| | - Atsushi Yamada
- Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan
| | - Mitsuhiro Kinoshita
- Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan
| | - Kentaro Yoshimura
- Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan
| | - Ryota Kawai
- Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan; Department of Orthodontics, Showa University School of Dentistry, Tokyo, Japan
| | - Fumiko Yano
- Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan
| | - Tatsuo Shirota
- Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Tokyo, Japan
| | - Ryutaro Kamijo
- Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan
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Abstract
Osteocytes, former osteoblasts encapsulated by mineralized bone matrix, are far from being passive and metabolically inactive bone cells. Instead, osteocytes are multifunctional and dynamic cells capable of integrating hormonal and mechanical signals and transmitting them to effector cells in bone and in distant tissues. Osteocytes are a major source of molecules that regulate bone homeostasis by integrating both mechanical cues and hormonal signals that coordinate the differentiation and function of osteoclasts and osteoblasts. Osteocyte function is altered in both rare and common bone diseases, suggesting that osteocyte dysfunction is directly involved in the pathophysiology of several disorders affecting the skeleton. Advances in osteocyte biology initiated the development of novel therapeutics interfering with osteocyte-secreted molecules. Moreover, osteocytes are targets and key distributors of biological signals mediating the beneficial effects of several bone therapeutics used in the clinic. Here we review the most recent discoveries in osteocyte biology demonstrating that osteocytes regulate bone homeostasis and bone marrow fat via paracrine signaling, influence body composition and energy metabolism via endocrine signaling, and contribute to the damaging effects of diabetes mellitus and hematologic and metastatic cancers in the skeleton.
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Affiliation(s)
- Jesus Delgado-Calle
- 1Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas,2Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Teresita Bellido
- 1Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas,2Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas,3Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
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Shah M, Appuswamy AV, Rao SD, Dhaliwal R. Treatment of bone fragility in patients with diabetes: antiresorptive versus anabolic? Curr Opin Endocrinol Diabetes Obes 2021; 28:377-382. [PMID: 34010225 PMCID: PMC8244995 DOI: 10.1097/med.0000000000000645] [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] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW The pathogenesis of bone fragility in diabetes has not been fully characterized. The antifracture efficacy of available therapies remains unproven in patients with diabetes. We aim to collate current evidence of the treatment of diabetic bone fragility, and to provide a rationale for considering optimal therapeutic option in patients with diabetes. RECENT FINDINGS The antifracture efficacy of antiresorptive and anabolic therapies is well established in patients without diabetes. Studies in patients with osteoporosis have shown that anabolic therapies lead to faster and larger benefits to bone mineral density and offer greater protection against fracture than antiresorptive therapies. Available data suggest that antiresorptive and anabolic therapies have similar effect on bone density and fracture risk reduction in patients with and without diabetes. However, the evidence in diabetes is limited to observational studies and post hoc analyses of osteoporosis studies. SUMMARY There are no specific guidelines for the treatment of bone fragility in patients with diabetes. We offer a rationale for use of anabolic therapies in diabetes which is a low bone formation state, in contrast to postmenopausal osteoporosis that is characterized by increased bone turnover. Prospective studies evaluating the effect of available therapies on bone quality and fracture outcomes in patients with diabetes are needed.
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Affiliation(s)
- Meghna Shah
- Metabolic Bone Disease Center, State University of New York Upstate Medical University, NY
| | | | - Sudhaker D. Rao
- Bone and Mineral Research Laboratory, Henry Ford Hospital, Detroit, MI
| | - Ruban Dhaliwal
- Metabolic Bone Disease Center, State University of New York Upstate Medical University, NY
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Abstract
Diabetes-induced osteoporosis is characterized by an increase in fracture risk. FRAX, the most widely used tool, underestimates the risk of fracture in both type 1 and type 2 diabetes. Specific adjustments to FRAX can help to better identify patients with diabetes at increased risk of fracture and select those at high fracture risk for treatment. Although clinical trial data are limited, the available evidence indicates that the presence of diabetes does not alter antiosteoporotic treatment response in patients with diabetes.
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Affiliation(s)
- G Isanne Schacter
- Department of Medicine, Rady Faculty of Health Sciences, University of Manitoba, GF-335, 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9, Canada
| | - William D Leslie
- Department of Medicine, Rady Faculty of Health Sciences, University of Manitoba, C5121, 409 Tache Avenue, Winnipeg, Manitoba R2H 2A6, Canada.
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Baraghithy S, Soae Y, Assaf D, Hinden L, Udi S, Drori A, Gabet Y, Tam J. Renal Proximal Tubule Cell Cannabinoid-1 Receptor Regulates Bone Remodeling and Mass via a Kidney-to-Bone Axis. Cells 2021; 10:414. [PMID: 33671138 PMCID: PMC7922053 DOI: 10.3390/cells10020414] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/07/2021] [Accepted: 02/13/2021] [Indexed: 12/20/2022] Open
Abstract
The renal proximal tubule cells (RPTCs), well-known for maintaining glucose and mineral homeostasis, play a critical role in the regulation of kidney function and bone remodeling. Deterioration in RPTC function may therefore lead to the development of diabetic kidney disease (DKD) and osteoporosis. Previously, we have shown that the cannabinoid-1 receptor (CB1R) modulates both kidney function as well as bone remodeling and mass via its direct role in RPTCs and bone cells, respectively. Here we employed genetic and pharmacological approaches that target CB1R, and found that its specific nullification in RPTCs preserves bone mass and remodeling both under normo- and hyper-glycemic conditions, and that its chronic blockade prevents the development of diabetes-induced bone loss. These protective effects of negatively targeting CB1R specifically in RPTCs were associated with its ability to modulate erythropoietin (EPO) synthesis, a hormone known to affect bone mass and remodeling. Our findings highlight a novel molecular mechanism by which CB1R in RPTCs remotely regulates skeletal homeostasis via a kidney-to-bone axis that involves EPO.
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Affiliation(s)
- Saja Baraghithy
- Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel; (S.B.); (Y.S.); (D.A.); (L.H.); (S.U.); (A.D.)
| | - Yael Soae
- Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel; (S.B.); (Y.S.); (D.A.); (L.H.); (S.U.); (A.D.)
| | - Dekel Assaf
- Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel; (S.B.); (Y.S.); (D.A.); (L.H.); (S.U.); (A.D.)
| | - Liad Hinden
- Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel; (S.B.); (Y.S.); (D.A.); (L.H.); (S.U.); (A.D.)
| | - Shiran Udi
- Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel; (S.B.); (Y.S.); (D.A.); (L.H.); (S.U.); (A.D.)
| | - Adi Drori
- Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel; (S.B.); (Y.S.); (D.A.); (L.H.); (S.U.); (A.D.)
| | - Yankel Gabet
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel;
| | - Joseph Tam
- Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel; (S.B.); (Y.S.); (D.A.); (L.H.); (S.U.); (A.D.)
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Bone marrow fat: friend or foe in people with diabetes mellitus? Clin Sci (Lond) 2020; 134:1031-1048. [PMID: 32337536 DOI: 10.1042/cs20200220] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/15/2020] [Accepted: 04/20/2020] [Indexed: 12/22/2022]
Abstract
Global trends in the prevalence of overweight and obesity put the adipocyte in the focus of huge medical interest. This review highlights a new topic in adipose tissue biology, namely the emerging pathogenic role of fat accumulation in bone marrow (BM). Specifically, we summarize current knowledge about the origin and function of BM adipose tissue (BMAT), provide evidence for the association of excess BMAT with diabetes and related cardiovascular complications, and discuss potential therapeutic approaches to correct BMAT dysfunction. There is still a significant uncertainty about the origins and function of BMAT, although several subpopulations of stromal cells have been suggested to have an adipogenic propensity. BM adipocytes are higly plastic and have a distinctive capacity to secrete adipokines that exert local and endocrine functions. BM adiposity is abundant in elderly people and has therefore been interpreted as a component of the whole-body ageing process. BM senescence and BMAT accumulation has been also reported in patients and animal models with Type 2 diabetes, being more pronounced in those with ischaemic complications. Understanding the mechanisms responsible for excess and altered function of BMAT could lead to new treatments able to preserve whole-body homeostasis.
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12
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Yang J, Chen S, Zong Z, Yang L, Liu D, Bao Q, Du W. The increase in bone resorption in early-stage type I diabetic mice is induced by RANKL secreted by increased bone marrow adipocytes. Biochem Biophys Res Commun 2020; 525:433-439. [PMID: 32102755 DOI: 10.1016/j.bbrc.2020.02.079] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 02/12/2020] [Indexed: 12/11/2022]
Abstract
Bone marrow adipose tissue (BMAT) has recently been found to induce osteoclastogenesis by secreting RANKL. Although Type 1 diabetes mellitus (T1DM) has been reported to be associated with increased BMAT and bone loss, little is known about the relationship between BMAT and osteoclasts in T1DM. We studied the role of BMAT in the alterations of osteoclast activities in early-stage T1DM, by using a streptozotocin-induced T1DM mouse model. Our results showed that osteoclast activity was enhanced in the long bones of T1DM mice, accompanied by increased protein expression of RANKL. However, RANKL mRNA levels in bone tissues of T1DM mice remained unchanged. Meanwhile, we found that BMAT was significantly increased in the long bones of T1DM mice, and both mRNA and protein levels of RANKL were elevated in the diabetic BMAT. More importantly, RANKL protein was mainly expressed on the cell membranes of the increased adipocytes, most of which were located next to the metaphyseal region. These results suggest that the enhanced bone resorption in early-stage diabetic mice is induced by RANKL derived from BMAT rather than the bone tissue itself.
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Affiliation(s)
- Jiazhi Yang
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, ChongQing, 400038, PR China; Department of Orthopedics, Xinqiao Hospital, Army Medical University, ChongQing, 400037, PR China
| | - Sixu Chen
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, ChongQing, 400038, PR China; Department of Orthopedics, The 906th Hospital of the Chinese People's Liberation Army, Wenzhou, Zhejiang, 325000, PR China
| | - Zhaowen Zong
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, ChongQing, 400038, PR China; Department of Orthopedics, Xinqiao Hospital, Army Medical University, ChongQing, 400037, PR China.
| | - Lei Yang
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, ChongQing, 400038, PR China; Department of Orthopedics, Xinqiao Hospital, Army Medical University, ChongQing, 400037, PR China
| | - Daocheng Liu
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, ChongQing, 400038, PR China; Department of Orthopedics, Xinqiao Hospital, Army Medical University, ChongQing, 400037, PR China
| | - Quanwei Bao
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, ChongQing, 400038, PR China; Department of Emergency, Xinqiao Hospital, Army Medical University, ChongQing, 400037, PR China
| | - Wenqiong Du
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, ChongQing, 400038, PR China
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13
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Zhang Y, Shen X, Cheng L, Chen R, Zhao F, Zhong S, Lan C, Yan S. Toll-like receptor 4 knockout protects against diabetic-induced imbalance of bone metabolism via autophagic suppression. Mol Immunol 2020; 117:12-19. [DOI: 10.1016/j.molimm.2019.10.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 10/27/2019] [Accepted: 10/30/2019] [Indexed: 01/14/2023]
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14
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Abstract
PURPOSE OF REVIEW The goal of this review is to discuss the role of insulin signaling in bone marrow adipocyte formation, metabolic function, and its contribution to cellular senescence in relation to metabolic bone diseases. RECENT FINDINGS Insulin signaling is an evolutionally conserved signaling pathway that plays a critical role in the regulation of metabolism and longevity. Bone is an insulin-responsive organ that plays a role in whole body energy metabolism. Metabolic disturbances associated with obesity and type 2 diabetes increase a risk of fragility fractures along with increased bone marrow adiposity. In obesity, there is impaired insulin signaling in peripheral tissues leading to insulin resistance. However, insulin signaling is maintained in bone marrow microenvironment leading to hypermetabolic state of bone marrow stromal (skeletal) stem cells associated with accelerated senescence and accumulation of bone marrow adipocytes in obesity. This review summarizes current findings on insulin signaling in bone marrow adipocytes and bone marrow stromal (skeletal) stem cells and its importance for bone and fat metabolism. Moreover, it points out to the existence of differences between bone marrow and peripheral fat metabolism which may be relevant for developing therapeutic strategies for treatment of metabolic bone diseases.
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Affiliation(s)
- Michaela Tencerova
- Department of Molecular Endocrinology, KMEB, University of Southern Denmark and Odense University Hospital, 5000, Odense C, Denmark.
- Department of Molecular Physiology of Bone, Institute of Physiology, Czech Academy of Sciences, 142 20, Prague 4, Czech Republic.
| | - Meshail Okla
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Moustapha Kassem
- Department of Molecular Endocrinology, KMEB, University of Southern Denmark and Odense University Hospital, 5000, Odense C, Denmark
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Department of Cellular and Molecular Medicine, The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Panum Institute, University of Copenhagen, Copenhagen, Denmark
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15
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Ohuchi K, Miyakoshi N, Kasukawa Y, Segawa T, Kinoshita H, Sato C, Fujii M, Shimada Y. Effects of teriparatide on bone in autochthonous transgenic model mice for diabetes mellitus (Akita mice). Osteoporos Sarcopenia 2019; 5:109-115. [PMID: 31938729 PMCID: PMC6953529 DOI: 10.1016/j.afos.2019.11.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 11/10/2019] [Accepted: 11/23/2019] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVES The purpose of this study is to evaluate the effects of teriparatide (TPTD) on bone mineral density (BMD), bone strength, and bone quality in Akita mouse models of diabetes mellitus. METHODS Twelve-week-old female Akita mice and control mice (C57/BL/6NCrSlc) were divided into 4 groups: control mice treated with vehicle (n = 7) or TPTD (n = 6); and Akita mice treated with vehicle (n = 6) or TPTD (n = 7). TPTD or vehicle was administered subcutaneously 3 times a week for 8 weeks. Blood glucose, serum sclerostin, total tibial BMD, femoral shaft bone strength, and bone quality using Fourier-transform infrared spectroscopy imaging were evaluated. RESULTS No significant differences in serum sclerostin levels were evident among these groups after 8 weeks of treatment. TPTD significantly increased BMD in control mice (+12.7%, P = 0.02) and Akita mice (+29.2%, P = 0.001) compared with vehicle. Maximum load and stiffness were significantly higher in Akita mice treated with TPTD than in Akita mice treated with vehicle (+56.6%, P = 0.03 and + 90.5%, P = 0.02, respectively). On Fourier-transform infrared spectroscopy imaging, the mineral/matrix ratio was significantly lower in Akita mice treated with vehicle than in control mice (-12.2%, P = 0.02), and TPTD treatment significantly increased the mineral/matrix ratio (P = 0.003). CONCLUSIONS TPTD thus improved BMD and bone strength in both control mice and Akita mice, with improvements in the mineral/matrix ratio among Akita mice.
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Affiliation(s)
| | - Naohisa Miyakoshi
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Akita, Japan
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16
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Mohsin S, Kaimala S, AlTamimi EKY, Tariq S, Adeghate E. In vivo Labeling of Bone Microdamage in an Animal Model of Type 1 Diabetes Mellitus. Sci Rep 2019; 9:16994. [PMID: 31740777 PMCID: PMC6861243 DOI: 10.1038/s41598-019-53487-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 10/21/2019] [Indexed: 01/23/2023] Open
Abstract
Type 1 diabetes mellitus (DM1) is linked to a decrease in bone strength. Bone strength entails both bone mineral density and bone quality. Limited data are available regarding diabetes-induced microdamage, which can severely influence bone quality. This study has investigated bone microdamage as a measure of bone quality in an animal model of DM1. Microdamage in the neck of the femur was labelled in vivo using multiple fluorochromes at 4, 12 and 24 weeks after the onset of DM1. Microcracks were quantified and their morphology analyzed using microscopy techniques. The mean length of microcracks at 24 weeks, and crack numerical and surface densities were significantly higher (p < 0.05) 4 weeks after the onset of DM1 when compared with control. Diffuse damage density was highest at 12 weeks after the onset of DM1. The arrangement of the collagen fibrils became progressively more irregular from 4 to 24 weeks of DM. This is the first study to analyze microdamage in vivo at different time points of DM1. DM1is associated with microcracks from the early stage, however bone microstructure shows toughening mechanisms that arrest their growth but disease progression further deteriorates bone quality resulting in longer microcracks which may increase fracture risk.
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Affiliation(s)
- Sahar Mohsin
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box. 17666, UAE.
| | - Suneesh Kaimala
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box. 17666, UAE
| | - Eman Khamis Yousef AlTamimi
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box. 17666, UAE
| | - Saeed Tariq
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box. 17666, UAE
| | - Ernest Adeghate
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box. 17666, UAE
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17
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Liu JM, Zhu DL, Mu YM, Xia WB. Management of fracture risk in patients with diabetes-Chinese Expert Consensus. J Diabetes 2019; 11:906-919. [PMID: 31219236 DOI: 10.1111/1753-0407.12962] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/20/2019] [Accepted: 06/17/2019] [Indexed: 02/06/2023] Open
Affiliation(s)
- Jian-Min Liu
- Department of Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao-tong University School of Medicine, Shanghai, China
| | - Da-Long Zhu
- Department of Endocrinology, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Yi-Ming Mu
- Department of Endocrinology, The General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Wei-Bo Xia
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
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18
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Vargas‐Muñoz VM, Martínez‐Martínez A, Muñoz‐Islas E, Ramírez‐Rosas MB, Acosta‐González RI, Jiménez‐Andrade JM. Chronic administration of Cl‐amidine, a pan‐peptidylarginine deiminase inhibitor, does not reverse bone loss in two different murine models of osteoporosis. Drug Dev Res 2019; 81:93-101. [DOI: 10.1002/ddr.21608] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/24/2019] [Accepted: 09/26/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Virginia M. Vargas‐Muñoz
- Unidad Académica Multidisciplinaria Reynosa‐Aztlán, Universidad Autónoma de Tamaulipas Reynosa Tamaulipas Mexico
| | - Arisai Martínez‐Martínez
- Unidad Académica Multidisciplinaria Reynosa‐Aztlán, Universidad Autónoma de Tamaulipas Reynosa Tamaulipas Mexico
| | - Enriqueta Muñoz‐Islas
- Unidad Académica Multidisciplinaria Reynosa‐Aztlán, Universidad Autónoma de Tamaulipas Reynosa Tamaulipas Mexico
| | - Martha B. Ramírez‐Rosas
- Unidad Académica Multidisciplinaria Reynosa‐Aztlán, Universidad Autónoma de Tamaulipas Reynosa Tamaulipas Mexico
| | - Rosa I. Acosta‐González
- Unidad Académica Multidisciplinaria Reynosa‐Aztlán, Universidad Autónoma de Tamaulipas Reynosa Tamaulipas Mexico
| | - Juan M. Jiménez‐Andrade
- Unidad Académica Multidisciplinaria Reynosa‐Aztlán, Universidad Autónoma de Tamaulipas Reynosa Tamaulipas Mexico
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19
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Saad FA. Novel insights into the complex architecture of osteoporosis molecular genetics. Ann N Y Acad Sci 2019; 1462:37-52. [PMID: 31556133 DOI: 10.1111/nyas.14231] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 07/22/2019] [Accepted: 08/14/2019] [Indexed: 12/19/2022]
Abstract
Osteoporosis is a prevalent osteodegenerative disease and silent killer linked to a decrease in bone mass and decline of bone microarchitecture, due to impaired bone matrix mineralization, raising the risk of fracture. Nevertheless, the process of bone matrix mineralization is still an unsolved mystery. Osteoporosis is a polygenic disorder associated with genetic and environmental risk factors; however, the majority of genes associated with osteoporosis remain largely unknown. Several signaling pathways regulate bone mass; therefore, dysregulation of a single signaling pathway leads to metabolic bone disease owing to high or low bone mass. Parathyroid hormone, core-binding factor α-1 (Cbfa1), Wnt/β-catenin, the receptor activator of the nuclear factor kappa-B (NF-κB) ligand (RANKL), myostatin, and osteogenic exercise signaling pathways play pivotal roles in the regulation of bone mass. The myostatin signaling pathway increases bone resorption by activating the RANKL signaling pathway, whereas osteogenic exercise inhibits myostatin and sclerostin while inducing irisin that consequentially activates the Cbfa1 and Wnt/β-catenin bone formation pathways. The aims of this review are to summarize what is known about osteoporosis-related signaling pathways; define the role of these pathways in osteoporosis drug discovery; focus light on the link between bone, muscle, pancreas, and adipose integrative physiology and osteoporosis; and underline the emerging role of osteogenic exercise in the prevention of, and care for, osteoporosis, obesity, and diabetes.
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Affiliation(s)
- Fawzy Ali Saad
- Department of Orthopaedic Surgery, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts
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20
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Costantini S, Conte C. Bone health in diabetes and prediabetes. World J Diabetes 2019; 10:421-445. [PMID: 31523379 PMCID: PMC6715571 DOI: 10.4239/wjd.v10.i8.421] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 06/03/2019] [Accepted: 07/20/2019] [Indexed: 02/05/2023] Open
Abstract
Bone fragility has been recognized as a complication of diabetes, both type 1 diabetes (T1D) and type 2 diabetes (T2D), whereas the relationship between prediabetes and fracture risk is less clear. Fractures can deeply impact a diabetic patient's quality of life. However, the mechanisms underlying bone fragility in diabetes are complex and have not been fully elucidated. Patients with T1D generally exhibit low bone mineral density (BMD), although the relatively small reduction in BMD does not entirely explain the increase in fracture risk. On the contrary, patients with T2D or prediabetes have normal or even higher BMD as compared with healthy subjects. These observations suggest that factors other than bone mass may influence fracture risk. Some of these factors have been identified, including disease duration, poor glycemic control, presence of diabetes complications, and certain antidiabetic drugs. Nevertheless, currently available tools for the prediction of risk inadequately capture diabetic patients at increased risk of fracture. Aim of this review is to provide a comprehensive overview of bone health and the mechanisms responsible for increased susceptibility to fracture across the spectrum of glycemic status, spanning from insulin resistance to overt forms of diabetes. The management of bone fragility in diabetic patient is also discussed.
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Affiliation(s)
- Silvia Costantini
- Department of Immunology, Transplantation and Infectious Diseases, Vita-Salute San Raffaele University, Milan 20123, Italy
- Epatocentro Ticino, Lugano 6900, Switzerland
| | - Caterina Conte
- Department of Immunology, Transplantation and Infectious Diseases, Vita-Salute San Raffaele University, Milan 20123, Italy
- IRCCS Ospedale San Raffaele, Internal Medicine and Transplantation, Milan 20123, Italy
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21
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Chen S, Yang L, He S, Yang J, Liu D, Bao Q, Qin H, Du W, Zhong X, Chen C, Zong Z. Preactivation of β-catenin in osteoblasts improves the osteoanabolic effect of PTH in type 1 diabetic mice. J Cell Physiol 2019; 235:1480-1493. [PMID: 31301073 DOI: 10.1002/jcp.29068] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 06/18/2019] [Indexed: 12/23/2022]
Abstract
Type 1 diabetes (T1D) is correlated with osteopenia primarily due to low bone formation. Parathyroid hormone (PTH) is a known anabolic agent for bone, the anabolic effects of which are partially mediated through the Wnt/β-catenin signaling pathway. In the present study, we first determined the utility of intermittent PTH treatment in a streptozotocin-induced T1D mouse model. It was shown that the PTH-induced anabolic effects on bone mass and bone formation were attenuated in T1D mice compared with nondiabetic mice. Further, PTH treatment failed to activate β-catenin signaling in osteoblasts of T1D mice and was unable to improve osteoblast proliferation and differentiation. Next, the Col1-3.2 kb-CreERTM; β-cateninfx(ex3) mice were used to conditionally activate β-catenin in osteoblasts by injecting tamoxifen, and we addressed whether or not preactivation of β-catenin boosted the anabolic action of PTH on T1D-related bone loss. The results demonstrated that pretreatment with activation of osteoblastic β-catenin followed by PTH treatment outperformed PTH or β-catenin activation monotherapy and led to greatly improved bone structure, bone mass, and bone strength in this preclinical model of T1DM. Further analysis demonstrated that osteoblast proliferation and differentiation, as well as osteoprogenitors in the marrow, were all improved in the combination treatment group. These findings indicated a clear advantage of developing β-catenin as a target to improve the efficacy of PTH in the treatment of T1D-related osteopenia.
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Affiliation(s)
- Sixu Chen
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China.,Department of Orthopedics, The 118th Hospital of the Chinese People's Liberation Army, Zhejiang, Wenzhou, China
| | - Lei Yang
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China.,Department of Emergency, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Sihao He
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China.,Department of Emergency, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Jiazhi Yang
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China.,Department of Emergency, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Daocheng Liu
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China.,Department of Emergency, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Quanwei Bao
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China.,Department of Emergency, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Hao Qin
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China.,Department of Emergency, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Wenqiong Du
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China
| | - Xin Zhong
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China
| | - Can Chen
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China
| | - Zhaowen Zong
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China.,Department of Emergency, Xinqiao Hospital, Army Medical University, Chongqing, China
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22
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Schepper JD, Collins F, Rios-Arce ND, Raehtz S, Schaefer L, Gardinier JD, Britton R, Parameswaran N, McCabe LR. Probiotic Lactobacillus reuteri Prevents Postantibiotic Bone Loss by Reducing Intestinal Dysbiosis and Preventing Barrier Disruption. J Bone Miner Res 2019; 34:681-698. [PMID: 30690795 PMCID: PMC6557403 DOI: 10.1002/jbmr.3635] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/24/2018] [Accepted: 11/11/2018] [Indexed: 12/23/2022]
Abstract
Antibiotic treatment, commonly prescribed for bacterial infections, depletes and subsequently causes long-term alterations in intestinal microbiota composition. Knowing the importance of the microbiome in the regulation of bone density, we investigated the effect of postantibiotic treatment on gut and bone health. Intestinal microbiome repopulation at 4-weeks postantibiotic treatment resulted in an increase in the Firmicutes:Bacteroidetes ratio, increased intestinal permeability, and notably reduced femoral trabecular bone volume (approximately 30%, p < 0.01). Treatment with a mucus supplement (a high-molecular-weight polymer, MDY-1001 [MDY]) prevented the postantibiotic-induced barrier break as well as bone loss, indicating a mechanistic link between increased intestinal permeability and bone loss. A link between the microbiome composition and bone density was demonstrated by supplementing the mice with probiotic bacteria. Specifically, Lactobacillus reuteri, but not Lactobacillus rhamnosus GG or nonpathogenic Escherichia coli, reduced the postantibiotic elevation of the Firmicutes:Bacteroidetes ratio and prevented femoral and vertebral trabecular bone loss. Consistent with causing bone loss, postantibiotic-induced dysbiosis decreased osteoblast and increased osteoclast activities, changes that were prevented by both L. reuteri and MDY. These data underscore the importance of microbial dysbiosis in the regulation of intestinal permeability and bone health, as well as identify L. reuteri and MDY as novel therapies for preventing these adverse effects. © 2018 American Society for Bone and Mineral Research.
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Affiliation(s)
| | - Fraser Collins
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Naiomy Deliz Rios-Arce
- Department of Physiology, Michigan State University, East Lansing, Michigan
- Comparative Medicine and Integrative Biology Program, Michigan State University, East Lansing, Michigan
| | - Sandi Raehtz
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Laura Schaefer
- Department of Molecular Virology and Microbiology, Baylor College of Medicine
| | | | - Robert Britton
- Department of Molecular Virology and Microbiology, Baylor College of Medicine
| | - Narayanan Parameswaran
- Department of Physiology, Michigan State University, East Lansing, Michigan
- equal contribution and co-senior authors
| | - Laura R McCabe
- Department of Physiology, Michigan State University, East Lansing, Michigan
- equal contribution and co-senior authors
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23
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Reddi S, Mada SB, Kumar N, Kumar R, Ahmad N, Karvande A, Kapila S, Kapila R, Trivedi R. Antiosteopenic Effect of Buffalo Milk Casein-Derived Peptide (NAVPITPTL) in Ovariectomized Rats. Int J Pept Res Ther 2018. [DOI: 10.1007/s10989-018-9763-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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24
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Liang C, Peng S, Li J, Lu J, Guan D, Jiang F, Lu C, Li F, He X, Zhu H, Au DWT, Yang D, Zhang BT, Lu A, Zhang G. Inhibition of osteoblastic Smurf1 promotes bone formation in mouse models of distinctive age-related osteoporosis. Nat Commun 2018; 9:3428. [PMID: 30143635 PMCID: PMC6109183 DOI: 10.1038/s41467-018-05974-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 08/06/2018] [Indexed: 11/20/2022] Open
Abstract
Bone morphogenetic protein (BMP) signaling is essential for osteogenesis. However, recombinant human BMPs (rhBMPs) exhibit large inter-individual variations in local bone formation during clinical spinal fusion. Smurf1 ubiquitinates BMP downstream molecules for degradation. Here, we classify age-related osteoporosis based on distinct intraosseous BMP-2 levels and Smurf1 activity. One major subgroup with a normal BMP-2 level and elevated Smurf1 activity (BMP-2n/Smurf1e) shows poor response to rhBMP-2 during spinal fusion, when compared to another major subgroup with a decreased BMP-2 level and normal Smurf1 activity (BMP-2d/Smurf1n). We screen a chalcone derivative, i.e., 2-(4-cinnamoylphenoxy)acetic acid, which effectively inhibits Smurf1 activity and increases BMP signaling. For BMP-2n/Smurf1e mice, the chalcone derivative enhances local bone formation during spinal fusion. After conjugating to an osteoblast-targeting and penetrating oligopeptide (DSS)6, the chalcone derivative promotes systemic bone formation in BMP-2n/Smurf1e mice. This study demonstrates a precision medicine-based bone anabolic strategy for age-related osteoporosis. BMP promotes bone formation but its efficacy is limited in some patients. Here, the authors show that osteoporosis patients with a poor response to BMP have increased expression of Smurf1, which targets BMP effectors for degradation, and demonstrate that its chemical inhibition enhances BMP-mediated bone formation in mice.
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Affiliation(s)
- Chao Liang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.,Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.,Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, 518000, Shenzhen, China
| | - Songlin Peng
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.,Department of Spine Surgery, Shenzhen People's Hospital, Ji Nan University Second College of Medicine, 518020, Shenzhen, China
| | - Jie Li
- School of Chinese Medicine, Faculty of Medicine, Chinese University of Hong Kong, 999077, Hong Kong, SAR, China.,Clinical Medical Laboratory of Peking University Shenzhen Hospital, 518036, Shenzhen, China
| | - Jun Lu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.,Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.,Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, 518000, Shenzhen, China
| | - Daogang Guan
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.,Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.,Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, 518000, Shenzhen, China
| | - Feng Jiang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.,Zhejiang Pharmaceutical College, 315100, Ningbo, China
| | - Cheng Lu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.,Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.,Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, 518000, Shenzhen, China.,Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, 100700, Beijing, China
| | - Fangfei Li
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.,Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.,Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, 518000, Shenzhen, China
| | - Xiaojuan He
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.,Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.,Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, 518000, Shenzhen, China.,Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, 100700, Beijing, China
| | - Hailong Zhu
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China
| | - D W T Au
- Department of Biology and Chemistry, City University of Hong Kong, 999077, Hong Kong, SAR, China
| | - Dazhi Yang
- Department of Spine Surgery, Shenzhen People's Hospital, Ji Nan University Second College of Medicine, 518020, Shenzhen, China
| | - Bao-Ting Zhang
- School of Chinese Medicine, Faculty of Medicine, Chinese University of Hong Kong, 999077, Hong Kong, SAR, China.
| | - Aiping Lu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China. .,Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China. .,Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, 518000, Shenzhen, China. .,Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, 200032, Shanghai, China.
| | - Ge Zhang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China. .,Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China. .,Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, 518000, Shenzhen, China.
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25
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Thong EP, Catford S, Fletcher J, Wong P, Fuller PJ, Teede H, Milat F. Recurrent vertebral fractures in a young adult: a closer look at bone health in type 1 diabetes mellitus. Endocrinol Diabetes Metab Case Rep 2018; 2018:EDM180010. [PMID: 29770222 PMCID: PMC5948196 DOI: 10.1530/edm-18-0010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 04/19/2018] [Indexed: 01/18/2023] Open
Abstract
The association between type 1 diabetes mellitus (T1DM) and bone health has garnered interest over the years. Fracture risk is known to be increased in individuals with T1DM, although bone health assessment is not often performed in the clinical setting. We describe the case of a 21-year-old male with longstanding T1DM with multilevel vertebral fractures on imaging, after presenting with acute back pain without apparent trauma. Dual-energy X-ray absorptiometry (DXA) revealed significantly reduced bone mineral density at the lumbar spine and femoral neck. Extensive investigations for other secondary or genetic causes of osteoporosis were unremarkable, apart from moderate vitamin D deficiency. High-resolution peripheral quantitative computed tomography and bone biospy revealed significant alterations of trabecular bone microarchitecture. It later transpired that the patient had sustained vertebral fractures secondary to unrecognised nocturnal hypoglycaemic seizures. Intravenous zoledronic acid was administered for secondary fracture prevention. Despite anti-resorptive therapy, the patient sustained a new vertebral fracture after experiencing another hypoglycaemic seizure in his sleep. Bone health in T1DM is complex and not well understood. There are significant challenges in the assessment and management of osteoporosis in T1DM, particularly in young adults, where fracture prediction tools have not been validated. Clinicians should be aware of hypoglycaemia as a significant risk factor for fracture in patients with T1DM. Learning points Type 1 diabetes mellitus (T1DM) is a secondary cause of osteoporosis, characterised by reduced bone mass and disturbed bone microarchitecture.Hypoglycaemic seizures generate sufficient compression forces along the thoracic column and can cause fractures in individuals with compromised bone quality.Unrecognised hypoglycaemic seizures should be considered in patients with T1DM presenting with fractures without a history of trauma.Patients with T1DM have increased fracture risk and risk factors should be addressed. Evaluation of bone microarchitecture may provide further insights into mechanisms of fracture in T1DM.Further research is needed to guide the optimal screening and management of bone health in patients with T1DM.
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Affiliation(s)
- Eleanor P Thong
- Department of Endocrinology, Monash Health, Clayton, Australia.,Monash Centre for Health Research and Implementation, Clayton, Australia
| | - Sarah Catford
- Department of Endocrinology, Monash Health, Clayton, Australia.,Hudson Institute of Medical Research, Clayton, Australia
| | - Julie Fletcher
- Department of Anatomical Pathology, Concord Repatriation General Hospital, Concord, Australia
| | - Phillip Wong
- Department of Endocrinology, Monash Health, Clayton, Australia.,Hudson Institute of Medical Research, Clayton, Australia
| | - Peter J Fuller
- Department of Endocrinology, Monash Health, Clayton, Australia.,Hudson Institute of Medical Research, Clayton, Australia
| | - Helena Teede
- Department of Endocrinology, Monash Health, Clayton, Australia.,Monash Centre for Health Research and Implementation, Clayton, Australia
| | - Frances Milat
- Department of Endocrinology, Monash Health, Clayton, Australia.,Hudson Institute of Medical Research, Clayton, Australia
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26
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Kalyanaraman H, Schwaerzer G, Ramdani G, Castillo F, Scott BT, Dillmann W, Sah RL, Casteel DE, Pilz RB. Protein Kinase G Activation Reverses Oxidative Stress and Restores Osteoblast Function and Bone Formation in Male Mice With Type 1 Diabetes. Diabetes 2018; 67:607-623. [PMID: 29301852 PMCID: PMC5860855 DOI: 10.2337/db17-0965] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 12/28/2017] [Indexed: 12/12/2022]
Abstract
Bone loss and fractures are underrecognized complications of type 1 diabetes and are primarily due to impaired bone formation by osteoblasts. The mechanisms leading to osteoblast dysfunction in diabetes are incompletely understood, but insulin deficiency, poor glycemic control, and hyperglycemia-induced oxidative stress likely contribute. Here we show that insulin promotes osteoblast proliferation and survival via the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) signal transduction pathway and that PKG stimulation of Akt provides a positive feedback loop. In osteoblasts exposed to high glucose, NO/cGMP/PKG signaling was reduced due in part to the addition of O-linked N-acetylglucosamine to NO synthase-3, oxidative inhibition of guanylate cyclase activity, and suppression of PKG transcription. Cinaciguat-an NO-independent activator of oxidized guanylate cyclase-increased cGMP synthesis under diabetic conditions and restored proliferation, differentiation, and survival of osteoblasts. Cinaciguat increased trabecular and cortical bone in mice with type 1 diabetes by improving bone formation and osteocyte survival. In bones from diabetic mice and in osteoblasts exposed to high glucose, cinaciguat reduced oxidative stress via PKG-dependent induction of antioxidant genes and downregulation of excess NADPH oxidase-4-dependent H2O2 production. These results suggest that cGMP-elevating agents could be used as an adjunct treatment for diabetes-associated osteoporosis.
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Affiliation(s)
- Hema Kalyanaraman
- Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Gerburg Schwaerzer
- Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Ghania Ramdani
- Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Francine Castillo
- Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Brian T Scott
- Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Wolfgang Dillmann
- Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Robert L Sah
- Department of Bioengineering, University of California, San Diego, La Jolla, CA
| | - Darren E Casteel
- Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Renate B Pilz
- Department of Medicine, University of California, San Diego, La Jolla, CA
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27
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Kim JH, Kim AR, Choi YH, Kim A, Sohn Y, Woo GH, Cha JH, Bak EJ, Yoo YJ. Intermittent PTH administration improves alveolar bone formation in type 1 diabetic rats with periodontitis. J Transl Med 2018; 16:70. [PMID: 29544500 PMCID: PMC5856320 DOI: 10.1186/s12967-018-1438-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 03/05/2018] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Periodontitis is an infectious disease that manifests as alveolar bone loss surrounding the roots of teeth. Diabetes aggravates periodontitis-induced alveolar bone loss via suppression of bone formation. Intermittent parathyroid hormone (PTH) administration displays an anabolic effect on bone. In this study, we investigated the effect of intermittent PTH administration on alveolar bone loss in type 1 diabetic rats with periodontitis. METHODS Rats were divided into control (C), periodontitis (P), periodontitis treated with PTH (P + PTH), diabetes with periodontitis (DP), and diabetes with periodontitis treated with PTH (DP + PTH) groups. To induce type 1 diabetes, rats were injected with streptozotocin and periodontitis was induced bilaterally by applying ligatures to the mandibular first molars for 30 days. During the experimental period, the P + PTH and DP + PTH groups were subcutaneously injected with PTH (40 μg/kg) three times per week, whereas the C, P, and DP groups were injected with citrate buffer. To observe the mineralization of the alveolar bone, the DP and DP + PTH groups were injected with calcein on days 10 and 27, and with alizarin red on day 20. Thirty days after ligation, histological findings and fluorescence labeling were analyzed in the furcations of the mandibular first molars. Sclerostin-positive osteocytes were assessed by immunohistochemical analyses. RESULTS The DP groups had smaller areas of alveolar bone than the other groups, and the DP + PTH group had a larger alveolar bone area than the DP group. The DP group had less osteoid formation than the C group, whereas the DP + PTH had greater osteoid formation than the DP group. Fluorescence labeling results revealed that the DP + PTH group had more mineral deposition on the alveolar bone than the DP group. The DP + PTH group exhibited lower percentage of sclerostin-positive osteocytes in alveolar bone than the DP group. CONCLUSIONS Intermittent PTH administration diminishes alveolar bone loss and sclerostin expression in osteocytes, but increases osteoid formation and mineralization, suggesting that intermittent PTH administration attenuates diabetes-aggravated alveolar bone loss by the induction of bone formation. PTH-induced bone formation may be related to the regulation of osteocytic sclerostin expression in type 1 diabetic rats with periodontitis.
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Affiliation(s)
- Ji-Hye Kim
- Department of Dental Hygiene, Jeonju Kijeon College, Jeonju, Republic of Korea
| | - Ae Ri Kim
- Department of Oral Biology, Yonsei University College of Dentistry, 134 Sinchon dong, Seodaemun-gu, Seoul, 120-752, Republic of Korea.,Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Republic of Korea.,BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Yun Hui Choi
- Department of Oral Biology, Yonsei University College of Dentistry, 134 Sinchon dong, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Aeryun Kim
- Department of Oral Biology, Yonsei University College of Dentistry, 134 Sinchon dong, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Yongsung Sohn
- DONG-A Pharm, Yongin-si, Gyeonggi-Do, Republic of Korea
| | - Gye-Hyeong Woo
- Department of Clinical Laboratory Science, Semyung University, Jecheon, Republic of Korea
| | - Jeong-Heon Cha
- Department of Oral Biology, Yonsei University College of Dentistry, 134 Sinchon dong, Seodaemun-gu, Seoul, 120-752, Republic of Korea.,Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Republic of Korea.,BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.,Microbiology and Molecular Biology, Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Eun-Jung Bak
- Department of Oral Biology, Yonsei University College of Dentistry, 134 Sinchon dong, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
| | - Yun-Jung Yoo
- Department of Oral Biology, Yonsei University College of Dentistry, 134 Sinchon dong, Seodaemun-gu, Seoul, 120-752, Republic of Korea. .,Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Republic of Korea.
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28
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Mabilleau G, Gobron B, Bouvard B, Chappard D. Incretin-based therapy for the treatment of bone fragility in diabetes mellitus. Peptides 2018; 100:108-113. [PMID: 29412811 DOI: 10.1016/j.peptides.2017.12.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 12/06/2017] [Accepted: 12/07/2017] [Indexed: 12/23/2022]
Abstract
Bone fractures are common comorbidities of type 2 diabetes mellitus (T2DM). Bone fracture incidence seems to develop due to increased risk of falls, poor bone quality and/or anti-diabetic medications. Previously, a relation between gut hormones and bone has been suspected. Most recent evidences suggest indeed that two gut hormones, namely glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), may control bone remodeling and quality. The GIP receptor is expressed in bone cells and knockout of either GIP or its receptor induces severe bone quality alterations. Similar alterations are also encountered in GLP-1 receptor knock-out animals associated with abnormal osteoclast resorption. Some GLP-1 receptor agonist (GLP-1RA) have been approved for the treatment of type 2 diabetes mellitus and although clinical trials may not have been designed to investigate bone fracture, first results suggest that GLP-1RA may not exacerbate abnormal bone quality observed in T2DM. The recent design of double and triple gut hormone agonists may also represent a suitable alternative for restoring compromised bone quality observed in T2DM. However, although most of these new molecules demonstrated weight loss action, little is known on their bone safety. The present review summarizes the most recent findings on peptide-based incretin therapy and bone physiology.
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Affiliation(s)
- Guillaume Mabilleau
- GEROM-LHEA UPRES EA4658, University of Angers, Institut de Biologie en Santé, Angers, France; SCIAM, University of Angers, Institut de Biologie en Santé, Angers, France; Bone Pathology Unit, Angers University Hospital, Angers, France.
| | - Benoît Gobron
- GEROM-LHEA UPRES EA4658, University of Angers, Institut de Biologie en Santé, Angers, France; Rheumatology Department, Angers University Hospital, Angers, France
| | - Béatrice Bouvard
- GEROM-LHEA UPRES EA4658, University of Angers, Institut de Biologie en Santé, Angers, France; Rheumatology Department, Angers University Hospital, Angers, France
| | - Daniel Chappard
- GEROM-LHEA UPRES EA4658, University of Angers, Institut de Biologie en Santé, Angers, France; SCIAM, University of Angers, Institut de Biologie en Santé, Angers, France; Bone Pathology Unit, Angers University Hospital, Angers, France
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29
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Chen H, Fu T, Ma Y, Wu X, Li X, Li X, Shen J, Wang H. Intermittent administration of parathyroid hormone ameliorated alveolar bone loss in experimental periodontitis in streptozotocin-induced diabetic rats. Arch Oral Biol 2017; 83:76-84. [DOI: 10.1016/j.archoralbio.2017.06.033] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 06/25/2017] [Accepted: 06/28/2017] [Indexed: 11/29/2022]
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30
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Carvalho AL, DeMambro VE, Guntur AR, Le P, Nagano K, Baron R, de Paula FJA, Motyl KJ. High fat diet attenuates hyperglycemia, body composition changes, and bone loss in male streptozotocin-induced type 1 diabetic mice. J Cell Physiol 2017. [PMID: 28631813 DOI: 10.1002/jcp.26062] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
There is a growing and alarming prevalence of obesity and the metabolic syndrome in type I diabetic patients (T1DM), particularly in adolescence. In general, low bone mass, higher fracture risk, and increased marrow adipose tissue (MAT) are features of diabetic osteopathy in insulin-deficient subjects. On the other hand, type 2 diabetes (T2DM) is associated with normal or high bone mass, a greater risk of peripheral fractures, and no change in MAT. Therefore, we sought to determine the effect of weight gain on bone turnover in insulin-deficient mice. We evaluated the impact of a 6-week high-fat (HFD) rich in medium chain fatty acids or low-fat diet (LFD) on bone mass and MAT in a streptozotocin (STZ)-induced model using male C57BL/6J mice at 8 weeks of age. Dietary intervention was initiated after diabetes confirmation. At the endpoint, lower non-fasting glucose levels were observed in diabetic mice fed with high fat diet compared to diabetic mice fed the low fat diet (STZ-LFD). Compared to euglycemic controls, the STZ-LFD had marked polydipsia and polyphagia, as well as reduced lean mass, fat mass, and bone parameters. Interestingly, STZ-HFD mice had higher bone mass, namely less cortical bone loss and more trabecular bone than STZ-LFD. Thus, we found that a HFD, rich in medium chain fatty acids, protects against bone loss in a T1DM mouse model. Whether this may also translate to T1DM patients who are overweight or obese in respect to maintenance of bone mass remains to be determined through longitudinal studies.
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Affiliation(s)
- Adriana Lelis Carvalho
- Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, Maine.,Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Victoria E DeMambro
- Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, Maine
| | - Anyonya R Guntur
- Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, Maine
| | - Phuong Le
- Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, Maine
| | - Kenichi Nagano
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, Massachusetts
| | - Roland Baron
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, Massachusetts
| | | | - Katherine J Motyl
- Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, Maine.,Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine
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31
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Enríquez-Pérez IA, Galindo-Ordoñez KE, Pantoja-Ortíz CE, Martínez-Martínez A, Acosta-González RI, Muñoz-Islas E, Jiménez-Andrade JM. Streptozocin-induced type-1 diabetes mellitus results in decreased density of CGRP sensory and TH sympathetic nerve fibers that are positively correlated with bone loss at the mouse femoral neck. Neurosci Lett 2017; 655:28-34. [DOI: 10.1016/j.neulet.2017.06.042] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 06/09/2017] [Accepted: 06/23/2017] [Indexed: 10/19/2022]
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32
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Bartlow CM, Oest ME, Mann KA, Zimmerman ND, Butt BB, Damron TA. PTH(1-34) and zoledronic acid have differing longitudinal effects on juvenile mouse femur strength and morphology. J Orthop Res 2017; 35:1707-1715. [PMID: 27653318 PMCID: PMC5489362 DOI: 10.1002/jor.23442] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 09/15/2016] [Indexed: 02/04/2023]
Abstract
Treatment of secondary pediatric osteoporosis-particularly that due to chronic diseases, immobilization, and necessary medical treatments-is currently limited by a poor understanding of the long-term efficacy and safety of skeletal metabolism modifying drugs. This study aimed to characterize longitudinal effects of representative anabolic (parathyroid hormone, PTH) and anti-catabolic (zoledronic acid, ZA) drugs on skeletal morphology, mechanical strength, and growth in juvenile mice. BALB/cJ mice aged 4 weeks were given PTH(1-34) or vehicle (control) daily for 8 weeks, or 4 weekly doses of ZA, and evaluated at time points 0-26 weeks after treatment initiation. There were no enduring differences in body length or mass between treatment groups. ZA increased femur size as early as week 0, including increased distal femur bone volume and diaphyseal cross-sectional area, persisting through week 26. PTH treatment only transiently increased bone size, including distal femur volume at weeks 4-12. ZA decreased diaphyseal cortical tissue mineral density (TMD) at 12-26 weeks versus controls; PTH decreased TMD only at 2 weeks (vs. controls). ZA increased bending strength at 0-12 weeks and flexural strength at week 4 (vs. controls), but decreased flexural strength and modulus at week 26. PTH treatment increased bending strength only at 4 weeks, and did not affect flexural strength. Overall, ZA rapidly and persistently increased femur strength and size, but compromised bone material quality long-term. In healthy juvenile mice, limited-duration PTH treatment did not exert a strong anabolic effect, and had no adverse effects on femur strength, morphology, or growth. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1707-1715, 2017.
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Affiliation(s)
- Christopher M Bartlow
- Department of Orthopedic Surgery, Upstate Medical University, 750 East Adams Street, Syracuse, New York
| | - Megan E Oest
- Department of Orthopedic Surgery, Upstate Medical University, 750 East Adams Street, Syracuse, New York
| | - Kenneth A Mann
- Department of Orthopedic Surgery, Upstate Medical University, 750 East Adams Street, Syracuse, New York
| | - Nicholas D Zimmerman
- Department of Orthopedic Surgery, Upstate Medical University, 750 East Adams Street, Syracuse, New York
| | - Bilal B Butt
- Department of Orthopedic Surgery, Upstate Medical University, 750 East Adams Street, Syracuse, New York
| | - Timothy A Damron
- Department of Orthopedic Surgery, Upstate Medical University, 750 East Adams Street, Syracuse, New York
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33
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Raehtz S, Bierhalter H, Schoenherr D, Parameswaran N, McCabe LR. Estrogen Deficiency Exacerbates Type 1 Diabetes-Induced Bone TNF-α Expression and Osteoporosis in Female Mice. Endocrinology 2017; 158:2086-2101. [PMID: 28419209 PMCID: PMC5505215 DOI: 10.1210/en.2016-1821] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 04/11/2017] [Indexed: 12/30/2022]
Abstract
Estrogen deficiency after menopause is associated with rapid bone loss, osteoporosis, and increased fracture risk. Type 1 diabetes (T1D), characterized by hypoinsulinemia and hyperglycemia, is also associated with bone loss and increased fracture risk. With better treatment options, T1D patients are living longer; therefore, the number of patients having both T1D and estrogen deficiency is increasing. Little is known about the mechanistic impact of T1D in conjunction with estrogen deficiency on bone physiology and density. To investigate this, 11-week-old mice were ovariectomized (OVX), and T1D was induced by multiple low-dose streptozotocin injection. Microcomputed tomographic analysis indicated a marked reduction in trabecular bone volume fraction (BVF) in T1D-OVX mice (~82%) that was far greater than the reductions (~50%) in BVF in either the OVX and T1D groups. Osteoblast markers, number, and activity were significantly decreased in T1D-OVX mice, to a greater extent than either T1D or OVX mice. Correspondingly, marrow adiposity was significantly increased in T1D-OVX mouse bone. Bone expression analyses revealed that tumor necrosis factor (TNF)-α levels were highest in T1D-OVX mice and correlated with bone loss, and osteoblast and osteocyte death. In vitro studies indicate that estrogen deficiency and high glucose enhance TNF-α expression in response to inflammatory signals. Taken together, T1D combined with estrogen deficiency has a major effect on bone inflammation, which contributes to suppressed bone formation and osteoporosis. Understanding the mechanisms/effects of estrogen deficiency in the presence of T1D on bone health is essential for fracture prevention in this patient population.
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Affiliation(s)
- Sandi Raehtz
- Department of Physiology, Michigan State University, East Lansing, Michigan 48824
| | - Hayley Bierhalter
- Department of Physiology, Michigan State University, East Lansing, Michigan 48824
| | - Daniel Schoenherr
- Department of Physiology, Michigan State University, East Lansing, Michigan 48824
| | | | - Laura R. McCabe
- Department of Physiology, Michigan State University, East Lansing, Michigan 48824
- Department of Radiology, Michigan State University, East Lansing, Michigan 48824
- Biomedical Imaging Research Center, Michigan State University, East Lansing, Michigan 48824
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34
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Zhang Y, Liu M, Li H, Chen Z, Liang N, Xu J, Zhang X, Zhang Y. Traditional Chinese medicine Bushen-Jianpi-Huoxue decoction prevents diabetic osteoporosis in rats via Wnt and nuclear factor-kappa B signaling pathways. Int J Rheum Dis 2017; 20:941-948. [PMID: 28294540 DOI: 10.1111/1756-185x.13050] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Yongqing Zhang
- Department of Orthopedics; Shouguang Traditional Chinese Medicine Hospital; Shouguang China
| | - Mingming Liu
- Department of Endocrinology; Shouguang Traditional Chinese Medicine Hospital; Shouguang China
| | - Haisheng Li
- Department of Orthopedics; Shouguang Traditional Chinese Medicine Hospital; Shouguang China
| | - Zetao Chen
- Department of Healthcare; Affiliated Hospital of ShanDong University of TCM; Jinan Shandong China
| | - Na Liang
- Department of Traditional Chinese Medicine; Shandong Provincial Qianfoshan Hospital; Jinan Shandong China
| | - Jianguo Xu
- Department of Traditional Chinese Medicine; Taishan Coal Sanatorum; Taian China
| | - Xiaoli Zhang
- Department of Endocrinology; Affiliated Hospital of Shandong University of Traditional Chinese Medicine; Jinan Shandong China
| | - Yihang Zhang
- Shandong Academy of Medical Sciences; Jinan Shandong China
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35
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Maycas M, McAndrews KA, Sato AY, Pellegrini GG, Brown DM, Allen MR, Plotkin LI, Gortazar AR, Esbrit P, Bellido T. PTHrP-Derived Peptides Restore Bone Mass and Strength in Diabetic Mice: Additive Effect of Mechanical Loading. J Bone Miner Res 2017; 32:486-497. [PMID: 27683064 DOI: 10.1002/jbmr.3007] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 09/23/2016] [Accepted: 09/27/2016] [Indexed: 01/17/2023]
Abstract
There is an unmet need to understand the mechanisms underlying skeletal deterioration in diabetes mellitus (DM) and to develop therapeutic approaches to treat bone fragility in diabetic patients. We demonstrate herein that mice with type 1 DM induced by streptozotocin exhibited low bone mass, inferior mechanical and material properties, increased bone resorption, decreased bone formation, increased apoptosis of osteocytes, and increased expression of the osteocyte-derived bone formation inhibitor Sost/sclerostin. Further, short treatment of diabetic mice with parathyroid hormone related protein (PTHrP)-derived peptides corrected these changes to levels undistinguishable from non-diabetic mice. In addition, diabetic mice exhibited reduced bone formation in response to mechanical stimulation, which was corrected by treatment with the PTHrP peptides, and higher prevalence of apoptotic osteocytes, which was reduced by loading or by the PTHrP peptides alone and reversed by a combination of loading and PTHrP peptide treatment. In vitro experiments demonstrated that the PTHrP peptides or mechanical stimulation by fluid flow activated the survival kinases ERKs and induced nuclear translocation of the canonical Wnt signaling mediator β-catenin, and prevented the increase in osteocytic cell apoptosis induced by high glucose. Thus, PTHrP-derived peptides cross-talk with mechanical signaling pathways to reverse skeletal deterioration induced by DM in mice. These findings suggest a crucial role of osteocytes in the harmful effects of diabetes on bone and raise the possibility of targeting these cells as a novel approach to treat skeletal deterioration in diabetes. Moreover, our study suggests the potential therapeutic efficacy of combined pharmacological and mechanical stimuli to promote bone accrual and maintenance in diabetic subjects. © 2016 American Society for Bone and Mineral Research.
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Affiliation(s)
- Marta Maycas
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.,Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain
| | - Kevin A McAndrews
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.,Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
| | - Amy Y Sato
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Gretel G Pellegrini
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Drew M Brown
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Matthew R Allen
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Lilian I Plotkin
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.,Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
| | - Arancha R Gortazar
- Instituto de Medicina Molecular Aplicada-Universidad San Pablo CEU, Madrid, Spain
| | - Pedro Esbrit
- Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain
| | - Teresita Bellido
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.,Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.,Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
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36
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Abstract
The World Health Organization estimates that diabetes mellitus occurs in more than 415 million people; this number could double by the year 2040. Epidemiologic data have shown that the skeletal system may be a target of diabetes-mediated damage, leading to the development of diabetes-induced osteoporosis. T1D and T2D have been associated with an increased risk of fracture. Bone mineral density and fracture risk prediction tools developed for the general population capture some of the risk associated with diabetes. Recent adaptations to these tools have improved their efficacy in patients with diabetes.
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Affiliation(s)
- G Isanne Schacter
- Department of Medicine, University of Manitoba, GF-335, 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9, Canada
| | - William D Leslie
- Department of Medicine, University of Manitoba, C5121, 409 Tache Avenue, Winnipeg, Manitoba R2H 2A6, Canada.
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37
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Schwartz AV. Efficacy of Osteoporosis Therapies in Diabetic Patients. Calcif Tissue Int 2017; 100:165-173. [PMID: 27461216 DOI: 10.1007/s00223-016-0177-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 07/12/2016] [Indexed: 12/30/2022]
Abstract
Diabetes is characterized by increased fracture risk and by reduced bone strength for a given density. Contributing factors may include lower bone turnover and accumulation of advanced glycation endproducts. There are concerns that the pharmacological therapies for osteoporosis, particularly anti-resorptive therapies that suppress bone turnover, may not be as effective in the setting of diabetes. This review considers clinical trials and observational studies that have assessed the efficacy of anti-resorptive and anabolic therapies in diabetic patients. Post hoc analyses of randomized trials indicate that raloxifene has similar efficacy for prevention of vertebral fractures in diabetic compared with non-diabetic patients. Evidence from randomized clinical trials is lacking for anti-fracture efficacy of other osteoporosis therapies in diabetes. However, observational studies suggest that bisphosphonates are effective in preventing fractures in diabetic patients. The great majority of diabetic patients in studies to date have been type 2, and efficacy of osteoporosis therapies in type 1 diabetic patients remains to be addressed. Further evaluation of the efficacy of osteoporosis therapies in the setting of diabetes is needed to provide optimal fracture prevention for this population.
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Affiliation(s)
- Ann V Schwartz
- Department of Epidemiology and Biostatistics, University of California San Francisco, Box 0560, San Francisco, CA, 94143, USA.
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38
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Sundararaghavan V, Mazur MM, Evans B, Liu J, Ebraheim NA. Diabetes and bone health: latest evidence and clinical implications. Ther Adv Musculoskelet Dis 2017; 9:67-74. [PMID: 28344668 DOI: 10.1177/1759720x16687480] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
As the prevalence of diabetes is increasing worldwide, research on some of the lesser-known effects, including impaired bone health, are gaining a lot of attention. The two most common forms of diabetes are type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). These two differ in their physiology, with T1DM stemming from an inability to produce insulin, and T2DM involving an insufficient response to the insulin that is produced. This review aims to highlight the most current information regarding diabetes as it relates to bone health. It looks at biochemical changes that characterize diabetic bone; notably increased adiposity, altered bone metabolism, and variations in bone mineral density (BMD). Then several hypotheses are analyzed, concerning how these changes may be detrimental to the highly orchestrated processes that are involved in bone formation and turnover, and ultimately result in the distinguishing features of diabetic bone. The review proceeds by explaining the effects of antidiabetes medications on bone health, then highlighting several ways that diabetes can play a part in other clinical treatment outcomes. With diabetes negatively affecting bone health and creating other clinical problems, and its treatment options potentiating these effects, physicians should consider the use of anti-osteoporotic drugs to supplement standard anti-diabetes medications in patients suffering with diabetic bone loss.
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Affiliation(s)
| | - Matthew M Mazur
- Department of Orthopaedic Surgery, University of Toledo Medical Center, Toledo, OH, USA
| | - Brad Evans
- Department of Orthopaedic Surgery, University of Toledo Medical Center, Toledo, OH, USA
| | - Jiayong Liu
- Department of Orthopaedic Surgery, University of Toledo Medical Center, 3065 Arlington Avenue, Toledo, OH 43614, USA
| | - Nabil A Ebraheim
- Department of Orthopaedic Surgery, University of Toledo Medical Center, Toledo, OH, USA
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39
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Iyer S, Han L, Ambrogini E, Yavropoulou M, Fowlkes J, Manolagas SC, Almeida M. Deletion of FoxO1, 3, and 4 in Osteoblast Progenitors Attenuates the Loss of Cancellous Bone Mass in a Mouse Model of Type 1 Diabetes. J Bone Miner Res 2017; 32:60-69. [PMID: 27491024 PMCID: PMC5492385 DOI: 10.1002/jbmr.2934] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 07/25/2016] [Accepted: 07/27/2016] [Indexed: 12/12/2022]
Abstract
Type 1 diabetes is associated with osteopenia and increased fragility fractures, attributed to reduced bone formation. However, the molecular mechanisms mediating these effects remain unknown. Insulin promotes osteoblast formation and inhibits the activity of the FoxO transcription factors. FoxOs, on the other hand, inhibit osteoprogenitor proliferation and bone formation. Here, we investigated whether FoxOs play a role in the low bone mass associated with type 1 diabetes, using mice lacking FoxO1, 3, and 4 in osteoprogenitor cells (FoxO1,3,4ΔOsx1-Cre ). Streptozotocin-induced diabetes caused a reduction in bone mass and strength in FoxO-intact mice. In contrast, cancellous bone was unaffected in diabetic FoxO1,3,4ΔOsx1-Cre mice. The low bone mass in the FoxO-intact diabetic mice was associated with decreased osteoblast number and bone formation, as well as decreased expression of the anti-osteoclastogenic cytokine osteoprotegerin (OPG) and increased osteoclast number. FoxO deficiency did not alter the effects of diabetes on bone formation; however, it did prevent the decrease in OPG and the increase in osteoclast number. Addition of high glucose to osteoblastic cell cultures decreased OPG mRNA, indicating that hyperglycemia in and of itself contributes to diabetic bone loss. Taken together, these results suggest that FoxOs exacerbate the loss of cancellous bone mass associated with type 1 diabetes and that inactivation of FoxOs might ameliorate the adverse effects of insulin deficiency. © 2016 American Society for Bone and Mineral Research.
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Affiliation(s)
- Srividhya Iyer
- Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
| | - Li Han
- Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
| | - Elena Ambrogini
- Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
| | - Maria Yavropoulou
- Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
| | - John Fowlkes
- Barnstable Brown Diabetes and Obesity Center, Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Stavros C Manolagas
- Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
| | - Maria Almeida
- Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
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40
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Kalaitzoglou E, Popescu I, Bunn RC, Fowlkes JL, Thrailkill KM. Effects of Type 1 Diabetes on Osteoblasts, Osteocytes, and Osteoclasts. Curr Osteoporos Rep 2016; 14:310-319. [PMID: 27704393 PMCID: PMC5106298 DOI: 10.1007/s11914-016-0329-9] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
PURPOSE OF REVIEW To describe the effects of type 1 diabetes on bone cells. RECENT FINDINGS Type 1 diabetes (T1D) is associated with low bone mineral density, increased risk of fractures, and poor fracture healing. Its effects on the skeleton were primarily attributed to impaired bone formation, but recent data suggests that bone remodeling and resorption are also compromised. The hyperglycemic and inflammatory environment associated with T1D impacts osteoblasts, osteocytes, and osteoclasts. The mechanisms involved are complex; insulinopenia, pro-inflammatory cytokine production, and alterations in gene expression are a few of the contributing factors leading to poor osteoblast activity and survival and, therefore, poor bone formation. In addition, the observed sclerostin level increase accompanied by decreased osteocyte number and enhanced osteoclast activity in T1D results in uncoupling of bone remodeling. T1D negatively impacts osteoblasts and osteocytes, whereas its effects on osteoclasts are not well characterized, although the limited studies available indicate increased osteoclast activity, favoring bone resorption.
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Affiliation(s)
- Evangelia Kalaitzoglou
- UK Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, 830 S. Limestone St., Lexington, KY, 40536, USA.
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
| | - Iuliana Popescu
- UK Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, 830 S. Limestone St., Lexington, KY, 40536, USA
| | - R Clay Bunn
- UK Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, 830 S. Limestone St., Lexington, KY, 40536, USA
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - John L Fowlkes
- UK Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, 830 S. Limestone St., Lexington, KY, 40536, USA
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Kathryn M Thrailkill
- UK Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, 830 S. Limestone St., Lexington, KY, 40536, USA
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
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41
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Ghodsi M, Larijani B, Keshtkar AA, Nasli-Esfahani E, Alatab S, Mohajeri-Tehrani MR. Mechanisms involved in altered bone metabolism in diabetes: a narrative review. J Diabetes Metab Disord 2016; 15:52. [PMID: 27891497 PMCID: PMC5111345 DOI: 10.1186/s40200-016-0275-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 11/01/2016] [Indexed: 02/08/2023]
Abstract
Many studies have shown that change in metabolism caused by diabetes can influence the bone metabolism in a way that quality and strength of bone is decreased. A 6 times and 2 times increased risk of fracture is reported in patients with type 1 and type 2 diabetes, respectively. There are several mechanisms by which diabetes can affect the bone. The fact that some of these mechanisms are acting in opposite ways opens the door for debate on pathways by which diabetes affects the bones. On the other hand, bone is not a simple organ that only get influence from other organs, but it is an endocrine organ that by secreting the agents such as osteocalcin, adiponectin and visfatin which can affect the insulin sensitivity and metabolism. In this paper we tried to briefly assess the latest finding in this matter.
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Affiliation(s)
- Maryam Ghodsi
- Diabetes Research Center (DRC), Endocrinology and Metabolism Research Institute (EMRI), Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center (EMRC), Endocrinology and Metabolism Resarch Institute (EMRI), Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Abbass Ali Keshtkar
- Department of Health Sciences Education Development, School of Public Health (SPH), Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Ensieh Nasli-Esfahani
- Diabetes Research Center (DRC), Endocrinology and Metabolism Research Institute (EMRI), Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Sudabeh Alatab
- Urology Research Center (URC), Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mohammad Reza Mohajeri-Tehrani
- Endocrinology and Metabolism Research Center (EMRC), Endocrinology and Metabolism Resarch Institute (EMRI), Tehran University of Medical Sciences (TUMS), Tehran, Iran
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42
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Seref-Ferlengez Z, Suadicani SO, Thi MM. A new perspective on mechanisms governing skeletal complications in type 1 diabetes. Ann N Y Acad Sci 2016; 1383:67-79. [PMID: 27571221 DOI: 10.1111/nyas.13202] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 07/11/2016] [Accepted: 07/18/2016] [Indexed: 12/29/2022]
Abstract
This review focuses on bone mechanobiology in type 1 diabetes (T1D), an area of research on diabetes-associated skeletal complications that is still in its infancy. We first provide a brief overview of the deleterious effects of diabetes on the skeleton and of the knowledge gained from studies with rodent models of T1D. Second, we discuss two specific hallmarks of T1D, low insulin and high glucose, and address the extent to which they affect skeletal health. Third, we highlight the mechanosensitive nature of bone tissue and the importance of mechanical loading for bone health. We also summarize recent advances in bone mechanobiology that implicate osteocytes as the mechanosensors and major regulatory cells in the bone. Finally, we discuss recent evidence indicating that the diabetic bone is "deaf" to mechanical loading and that osteocytes are central players in mechanisms that lead to bone loss in T1D.
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Affiliation(s)
- Zeynep Seref-Ferlengez
- Department of Orthopaedic Surgery.,Laboratories of Musculoskeletal Orthopedic Research at Einstein-Montefiore (MORE)
| | - Sylvia O Suadicani
- Laboratories of Musculoskeletal Orthopedic Research at Einstein-Montefiore (MORE).,Department of Neuroscience.,Department of Urology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York
| | - Mia M Thi
- Department of Orthopaedic Surgery.,Laboratories of Musculoskeletal Orthopedic Research at Einstein-Montefiore (MORE).,Department of Neuroscience
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43
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44
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Hull B, Smith NR. Diabetes and Bone. Am J Med Sci 2016; 351:356-60. [DOI: 10.1016/j.amjms.2016.02.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 02/01/2016] [Accepted: 02/05/2016] [Indexed: 12/30/2022]
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45
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Hough FS, Pierroz DD, Cooper C, Ferrari SL. MECHANISMS IN ENDOCRINOLOGY: Mechanisms and evaluation of bone fragility in type 1 diabetes mellitus. Eur J Endocrinol 2016; 174:R127-38. [PMID: 26537861 DOI: 10.1530/eje-15-0820] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 11/04/2015] [Indexed: 12/20/2022]
Abstract
Subjects with type 1 diabetes mellitus (T1DM) have decreased bone mineral density and an up to sixfold increase in fracture risk. Yet bone fragility is not commonly regarded as another unique complication of diabetes. Both animals with experimentally induced insulin deficiency syndromes and patients with T1DM have impaired osteoblastic bone formation, with or without increased bone resorption. Insulin/IGF1 deficiency appears to be a major pathogenetic mechanism involved, along with glucose toxicity, marrow adiposity, inflammation, adipokine and other metabolic alterations that may all play a role on altering bone turnover. In turn, increasing physical activity in children with diabetes as well as good glycaemic control appears to provide some improvement of bone parameters, although robust clinical studies are still lacking. In this context, the role of osteoporosis drugs remains unknown.
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Affiliation(s)
- F S Hough
- Division of EndocrinologyDepartment of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Stellenbosch, South AfricaInternational Osteoporosis Foundation (IOF)Nyon, SwitzerlandMRC Lifecourse Epidemiology UnitUniversity of Southampton, Southampton, UKNIHR Musculoskeletal Biomedical Research UnitNuffield Department of Orthopaedics, University of Oxford, Oxford, UKDivision of Bone DiseasesDepartment of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, 4, Rue Gabrielle-Perret-Gentil, 1211 Geneva 14, Switzerland
| | - D D Pierroz
- Division of EndocrinologyDepartment of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Stellenbosch, South AfricaInternational Osteoporosis Foundation (IOF)Nyon, SwitzerlandMRC Lifecourse Epidemiology UnitUniversity of Southampton, Southampton, UKNIHR Musculoskeletal Biomedical Research UnitNuffield Department of Orthopaedics, University of Oxford, Oxford, UKDivision of Bone DiseasesDepartment of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, 4, Rue Gabrielle-Perret-Gentil, 1211 Geneva 14, Switzerland
| | - C Cooper
- Division of EndocrinologyDepartment of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Stellenbosch, South AfricaInternational Osteoporosis Foundation (IOF)Nyon, SwitzerlandMRC Lifecourse Epidemiology UnitUniversity of Southampton, Southampton, UKNIHR Musculoskeletal Biomedical Research UnitNuffield Department of Orthopaedics, University of Oxford, Oxford, UKDivision of Bone DiseasesDepartment of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, 4, Rue Gabrielle-Perret-Gentil, 1211 Geneva 14, Switzerland Division of EndocrinologyDepartment of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Stellenbosch, South AfricaInternational Osteoporosis Foundation (IOF)Nyon, SwitzerlandMRC Lifecourse Epidemiology UnitUniversity of Southampton, Southampton, UKNIHR Musculoskeletal Biomedical Research UnitNuffield Department of Orthopaedics, University of Oxford, Oxford, UKDivision of Bone DiseasesDepartment of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, 4, Rue Gabrielle-Perret-Gentil, 1211 Geneva 14, Switzerland
| | - S L Ferrari
- Division of EndocrinologyDepartment of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Stellenbosch, South AfricaInternational Osteoporosis Foundation (IOF)Nyon, SwitzerlandMRC Lifecourse Epidemiology UnitUniversity of Southampton, Southampton, UKNIHR Musculoskeletal Biomedical Research UnitNuffield Department of Orthopaedics, University of Oxford, Oxford, UKDivision of Bone DiseasesDepartment of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, 4, Rue Gabrielle-Perret-Gentil, 1211 Geneva 14, Switzerland
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46
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Mansur SA, Mieczkowska A, Bouvard B, Flatt PR, Chappard D, Irwin N, Mabilleau G. Stable Incretin Mimetics Counter Rapid Deterioration of Bone Quality in Type 1 Diabetes Mellitus. J Cell Physiol 2015; 230:3009-18. [PMID: 26016732 DOI: 10.1002/jcp.25033] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 05/04/2015] [Indexed: 01/13/2023]
Abstract
Type 1 diabetes mellitus is associated with a high risk for bone fractures. Although bone mass is reduced, bone quality is also dramatically altered in this disorder. However, recent evidences suggest a beneficial effect of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) pathways on bone quality. The aims of the present study were to conduct a comprehensive investigation of bone strength at the organ and tissue level; and to ascertain whether enzyme resistant GIP or GLP-1 mimetic could be beneficial in preventing bone fragility in type 1 diabetes mellitus. Streptozotocin-treated mice were used as a model of type 1 diabetes mellitus. Control and streptozotocin-diabetic animals were treated for 21 days with an enzymatic-resistant GIP peptide ([D-Ala(2) ]GIP) or with liraglutide (each at 25 nmol/kg bw, ip). Bone quality was assessed at the organ and tissue level by microCT, qXRI, 3-point bending, qBEI, nanoindentation, and Fourier-transform infrared microspectroscopy. [D-Ala2]GIP and liraglutide treatment did prevent loss of whole bone strength and cortical microstructure in the STZ-injected mice. However, tissue material properties were significantly improved in STZ-injected animals following treatment with [D-Ala2]GIP or liraglutide. Treatment of STZ-diabetic mice with [D-Ala(2) ]GIP or liraglutide was capable of significantly preventing deterioration of the quality of the bone matrix. Further studies are required to further elucidate the molecular mechanisms involved and to validate whether these findings can be translated to human patients.
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Affiliation(s)
- Sity Aishah Mansur
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom.,University Tun Hussein Onn Malaysia, Johor, Malaysia
| | | | - Béatrice Bouvard
- GEROM-LHEA, Institut de Biologie en Santé, LUNAM Université, Angers, France
| | - Peter R Flatt
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
| | - Daniel Chappard
- GEROM-LHEA, Institut de Biologie en Santé, LUNAM Université, Angers, France.,SCIAM, Institut de Biologie en Santé, LUNAM Université, Angers, France
| | - Nigel Irwin
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
| | - Guillaume Mabilleau
- GEROM-LHEA, Institut de Biologie en Santé, LUNAM Université, Angers, France.,SCIAM, Institut de Biologie en Santé, LUNAM Université, Angers, France
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47
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Adverse Effects of Diabetes Mellitus on the Skeleton of Aging Mice. J Gerontol A Biol Sci Med Sci 2015; 71:290-9. [DOI: 10.1093/gerona/glv160] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 08/19/2015] [Indexed: 01/15/2023] Open
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48
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Zhang J, Motyl KJ, Irwin R, MacDougald OA, Britton RA, McCabe LR. Loss of Bone and Wnt10b Expression in Male Type 1 Diabetic Mice Is Blocked by the Probiotic Lactobacillus reuteri. Endocrinology 2015; 156:3169-82. [PMID: 26135835 PMCID: PMC4541610 DOI: 10.1210/en.2015-1308] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Type 1 diabetes (T1D)-induced osteoporosis is characterized by a predominant suppression of osteoblast number and activity, as well as increased bone marrow adiposity but no change in osteoclast activity. The fundamental mechanisms and alternative anabolic treatments (with few side effects) for T1D bone loss remain undetermined. Recent studies by our laboratory and others indicate that probiotics can benefit bone health. Here, we demonstrate that Lactobacillus reuteri, a probiotic with anti-inflammatory and bone health properties, prevents T1D-induced bone loss and marrow adiposity in mice. We further found that L. reuteri treatment prevented the suppression of Wnt10b in T1D bone. Consistent with a role for attenuated bone Wnt10b expression in T1D osteoporosis, we observed that bone-specific Wnt10b transgenic mice are protected from T1D bone loss. To examine the mechanisms of this protection, we focused on TNF-α, a cytokine up-regulated in T1D that causes suppression of osteoblast Wnt10b expression in vitro. Addition of L. reuteri prevented TNF-α-mediated suppression of Wnt10b and osteoblast maturation markers. Taken together, our findings reveal a mechanism by which T1D causes bone loss and open new avenues for use of probiotics to benefit the bone.
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Affiliation(s)
- Jing Zhang
- Department of Physiology (J.Z., K.J.M., R.I., L.R.M.), Department of Molecular and Integrative Physiology (O.A.M.), Department of Microbiology and Molecular Genetics (R.A.B.), Department of Radiology (L.R.M.), and Biomedical Imaging Research Center (L.R.M.), Michigan State University, East Lansing, Michigan 48824
| | - Katherine J Motyl
- Department of Physiology (J.Z., K.J.M., R.I., L.R.M.), Department of Molecular and Integrative Physiology (O.A.M.), Department of Microbiology and Molecular Genetics (R.A.B.), Department of Radiology (L.R.M.), and Biomedical Imaging Research Center (L.R.M.), Michigan State University, East Lansing, Michigan 48824
| | - Regina Irwin
- Department of Physiology (J.Z., K.J.M., R.I., L.R.M.), Department of Molecular and Integrative Physiology (O.A.M.), Department of Microbiology and Molecular Genetics (R.A.B.), Department of Radiology (L.R.M.), and Biomedical Imaging Research Center (L.R.M.), Michigan State University, East Lansing, Michigan 48824
| | - Ormond A MacDougald
- Department of Physiology (J.Z., K.J.M., R.I., L.R.M.), Department of Molecular and Integrative Physiology (O.A.M.), Department of Microbiology and Molecular Genetics (R.A.B.), Department of Radiology (L.R.M.), and Biomedical Imaging Research Center (L.R.M.), Michigan State University, East Lansing, Michigan 48824
| | - Robert A Britton
- Department of Physiology (J.Z., K.J.M., R.I., L.R.M.), Department of Molecular and Integrative Physiology (O.A.M.), Department of Microbiology and Molecular Genetics (R.A.B.), Department of Radiology (L.R.M.), and Biomedical Imaging Research Center (L.R.M.), Michigan State University, East Lansing, Michigan 48824
| | - Laura R McCabe
- Department of Physiology (J.Z., K.J.M., R.I., L.R.M.), Department of Molecular and Integrative Physiology (O.A.M.), Department of Microbiology and Molecular Genetics (R.A.B.), Department of Radiology (L.R.M.), and Biomedical Imaging Research Center (L.R.M.), Michigan State University, East Lansing, Michigan 48824
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Zhukouskaya VV, Eller-Vainicher C, Shepelkevich AP, Dydyshko Y, Cairoli E, Chiodini I. Bone health in type 1 diabetes: focus on evaluation and treatment in clinical practice. J Endocrinol Invest 2015; 38:941-50. [PMID: 25863666 DOI: 10.1007/s40618-015-0284-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Accepted: 03/31/2015] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Type 1 diabetes (T1D) is an autoimmune disease with chronic hyperglycemic state, which incidence has been globally rising during the past decades. Besides the well-known diabetic complications such as retinopathy, nephropathy and neuropathy, T1D is characterized also by poor bone health. The reduced bone mineralization, quality and strength lead to vertebral and hip fractures as the most important clinical manifestations. Suppressed bone turnover is the main characteristic of T1D-associated bone disorder. RESULTS This is thought to be due to hyperglycemia, hypoinsulinemia, autoimmune inflammation, low levels of insulin-like growth factor-1 and vitamin D. Young age of T1D manifestation, chronic poor glycemic control, high daily insulin dose, low body mass index, reduced renal function and the presence of diabetic complications are clinical factors useful for identifying T1D patients at risk of reduced bone mineral density. Although the clinical risk factors for fracture risk are still unknown, chronic poor glycemic control and the presence of diabetic complications might raise the suspicion of elevated fracture risk in T1D. In the presence of the above-mentioned risk factors, the assessment of bone mineral density by dual-energy X-ray absorptiometry and the search of asymptomatic vertebral fracture by vertebral fracture assessment or lateral X-ray radiography of thorax-lumbar spine should be recommended. CONCLUSION There is no consensus about the treatment of diabetic bone disorder. However, the improvement of glycemic control has been suggested to have a beneficial effect on bone in T1D. Recently, several experiments showed promising results on using anabolic pharmacological agents in diabetic rodents with bone disorder. Therefore, randomized clinical trials are needed to test the possible use of the bone anabolic therapies in humans with T1D.
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Affiliation(s)
- V V Zhukouskaya
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy,
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Lai X, Price C, Modla S, Thompson WR, Caplan J, Kirn-Safran CB, Wang L. The dependences of osteocyte network on bone compartment, age, and disease. Bone Res 2015; 3. [PMID: 26213632 PMCID: PMC4511381 DOI: 10.1038/boneres.2015.9] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Osteocytes, the most abundant bone cells, form an interconnected network in the lacunar-canalicular pore system (LCS) buried within the mineralized matrix, which allows osteocytes to obtain nutrients from the blood supply, sense external mechanical signals, and communicate among themselves and with other cells on bone surfaces. In this study, we examined key features of the LCS network including the topological parameter and the detailed structure of individual connections and their variations in cortical and cancellous compartments, at different ages, and in two disease conditions with altered mechanosensing (perlecan deficiency and diabetes). LCS network showed both topological stability, in terms of conservation of connectivity among osteocyte lacunae (similar to the "nodes" in a computer network), and considerable variability the pericellular annular fluid gap surrounding lacunae and canaliculi (similar to the "bandwidth" of individual links in a computer network). Age, in the range of our study (15-32 weeks), affected only the pericellular fluid annulus in cortical bone but not in cancellous bone. Diabetes impacted the spacing of the lacunae, while the perlecan deficiency had a profound influence on the pericellular fluid annulus. The LCS network features play important roles in osteocyte signaling and regulation of bone growth and adaptation.
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Affiliation(s)
- Xiaohan Lai
- Department of Mechanical Engineering, University of Delaware, Newark, DE, USA
| | - Christopher Price
- Biomedical Engineering Program, University of Delaware, Newark, DE, USA
| | - Shannon Modla
- DBI Bioimaging Center, University of Delaware, Newark, DE, USA
| | - William R Thompson
- Department of Physical Therapy, Indiana University, Indianapolis, IN, USA
| | - Jeffrey Caplan
- DBI Bioimaging Center, University of Delaware, Newark, DE, USA
| | | | - Liyun Wang
- Department of Mechanical Engineering, University of Delaware, Newark, DE, USA
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