|
1
|
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.
Collapse
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
| |
Collapse
|
|
2
|
Kupai K, Kang HL, Pósa A, Csonka Á, Várkonyi T, Valkusz Z. Bone Loss in Diabetes Mellitus: Diaporosis. Int J Mol Sci 2024; 25:7269. [PMID: 39000376 PMCID: PMC11242219 DOI: 10.3390/ijms25137269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 06/21/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
The objective of this review is to examine the connection between osteoporosis and diabetes, compare the underlying causes of osteoporosis in various forms of diabetes, and suggest optimal methods for diagnosing and assessing fracture risk in diabetic patients. This narrative review discusses the key factors contributing to the heightened risk of fractures in individuals with diabetes, as well as the shared elements impacting the treatment of both diabetes mellitus and osteoporosis. Understanding the close link between diabetes and a heightened risk of fractures is crucial in effectively managing both conditions. There are several review articles of meta-analysis regarding diaporosis. Nevertheless, no review articles showed collected and well-organized medications of antidiabetics and made for inconvenient reading for those who were interested in details of drug mechanisms. In this article, we presented collected and comprehensive charts of every antidiabetic medication which was linked to fracture risk and indicated plausible descriptions according to research articles.
Collapse
Affiliation(s)
- Krisztina Kupai
- Department of Internal Medicine, Albert Szent-Györgyi Medical School, University of Szeged, 6703 Szeged, Hungary
- Department of Oral Biology and Experimental Dental Research, Faculty of Dentistry, University of Szeged, 6703 Szeged, Hungary
| | - Hsu Lin Kang
- Department of Oral Biology and Experimental Dental Research, Faculty of Dentistry, University of Szeged, 6703 Szeged, Hungary
| | - Anikó Pósa
- Department of Oral Biology and Experimental Dental Research, Faculty of Dentistry, University of Szeged, 6703 Szeged, Hungary
| | - Ákos Csonka
- Department of Traumatology, University of Szeged, 6725 Szeged, Hungary;
| | - Tamás Várkonyi
- Department of Internal Medicine, Albert Szent-Györgyi Medical School, University of Szeged, 6703 Szeged, Hungary
| | - Zsuzsanna Valkusz
- Department of Internal Medicine, Albert Szent-Györgyi Medical School, University of Szeged, 6703 Szeged, Hungary
| |
Collapse
|
|
3
|
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.
Collapse
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.
| |
Collapse
|
|
4
|
Rubin MR, Dhaliwal R. Role of advanced glycation endproducts in bone fragility in type 1 diabetes. Bone 2024; 178:116928. [PMID: 37802378 DOI: 10.1016/j.bone.2023.116928] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 09/28/2023] [Accepted: 10/03/2023] [Indexed: 10/10/2023]
Abstract
The excess fracture risk observed in adults with type 1 diabetes (T1D) is inexplicable in the presence of only modest reductions in areal bone mineral density (BMD). Accumulation of advanced glycation endproducts (AGEs) in bone has been invoked as one explanation for the increased bone fragility in diabetes. The evidence linking AGEs and fractures in individuals with T1D is sparse, although the association has been observed in individuals with type 2 diabetes. Recent data show that in T1D, AGEs as measured by skin intrinsic fluorescence, are a risk factor for lower BMD. Further research in T1D is needed to ascertain whether there is a causal relationship between fractures and AGEs. If confirmed, this would pave the way for finding interventions that can slow AGE accumulation and thus reduce fractures in T1D.
Collapse
Affiliation(s)
- Mishaela R Rubin
- Metabolic Bone Disease Unit, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, United States of America
| | - Ruban Dhaliwal
- Division of Endocrinology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, United States of America.
| |
Collapse
|
|
5
|
Jiang H, Li D, Han Y, Li N, Tao X, Liu J, Zhang Z, Yu Y, Wang L, Yu S, Zhang N, Xiao H, Yang X, Zhang Y, Zhang G, Zhang BT. The role of sclerostin in lipid and glucose metabolism disorders. Biochem Pharmacol 2023; 215:115694. [PMID: 37481136 DOI: 10.1016/j.bcp.2023.115694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/01/2023] [Accepted: 07/11/2023] [Indexed: 07/24/2023]
Abstract
Lipid and glucose metabolism are critical for human activities, and their disorders can cause diabetes and obesity, two prevalent metabolic diseases. Studies suggest that the bone involved in lipid and glucose metabolism is emerging as an endocrine organ that regulates systemic metabolism through bone-derived molecules. Sclerostin, a protein mainly produced by osteocytes, has been therapeutically targeted by antibodies for treating osteoporosis owing to its ability to inhibit bone formation. Moreover, recent evidence indicates that sclerostin plays a role in lipid and glucose metabolism disorders. Although the effects of sclerostin on bone have been extensively examined and reviewed, its effects on systemic metabolism have not yet been well summarized. In this paper, we provide a systemic review of the effects of sclerostin on lipid and glucose metabolism based on in vitro and in vivo evidence, summarize the research progress on sclerostin, and prospect its potential manipulation for obesity and diabetes treatment.
Collapse
Affiliation(s)
- Hewen Jiang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Dijie Li
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Ying Han
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Nanxi Li
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Xiaohui Tao
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Jin Liu
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Zongkang Zhang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Yuanyuan Yu
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Luyao Wang
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Sifan Yu
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Ning Zhang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Huan Xiao
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Xin Yang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Yihao Zhang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Ge Zhang
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
| | - Bao-Ting Zhang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China.
| |
Collapse
|
|
6
|
Urbano F, Farella I, Brunetti G, Faienza MF. Pediatric Type 1 Diabetes: Mechanisms and Impact of Technologies on Comorbidities and Life Expectancy. Int J Mol Sci 2023; 24:11980. [PMID: 37569354 PMCID: PMC10418611 DOI: 10.3390/ijms241511980] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Type 1 diabetes (T1D) is one of the most common chronic diseases in childhood, with a progressively increasing incidence. T1D management requires lifelong insulin treatment and ongoing health care support. The main goal of treatment is to maintain blood glucose levels as close to the physiological range as possible, particularly to avoid blood glucose fluctuations, which have been linked to morbidity and mortality in patients with T1D. Indeed, the guidelines of the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommend a glycated hemoglobin (HbA1c) level < 53 mmol/mol (<7.0%) for young people with T1D to avoid comorbidities. Moreover, diabetic disease strongly influences the quality of life of young patients who must undergo continuous monitoring of glycemic values and the administration of subcutaneous insulin. In recent decades, the development of automated insulin delivery (AID) systems improved the metabolic control and the quality of life of T1D patients. Continuous subcutaneous insulin infusion (CSII) combined with continuous glucose monitoring (CGM) devices connected to smartphones represent a good therapeutic option, especially in young children. In this literature review, we revised the mechanisms of the currently available technologies for T1D in pediatric age and explored their effect on short- and long-term diabetes-related comorbidities, quality of life, and life expectation.
Collapse
Affiliation(s)
- Flavia Urbano
- Giovanni XXIII Pediatric Hospital, 70126 Bari, Italy;
| | - Ilaria Farella
- Clinica Medica “A. Murri”, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies, and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy
| | - Maria Felicia Faienza
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| |
Collapse
|
|
7
|
Bao K, Jiao Y, Xing L, Zhang F, Tian F. The role of wnt signaling in diabetes-induced osteoporosis. Diabetol Metab Syndr 2023; 15:84. [PMID: 37106471 PMCID: PMC10141960 DOI: 10.1186/s13098-023-01067-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 04/24/2023] [Indexed: 04/29/2023] Open
Abstract
Osteoporosis, a chronic complication of diabetes mellitus, is characterized by a reduction in bone mass, destruction of bone microarchitecture, decreased bone strength, and increased bone fragility. Because of its insidious onset, osteoporosis renders patients highly susceptible to pathological fractures, leading to increased disability and mortality rates. However, the specific pathogenesis of osteoporosis induced by chronic hyperglycemia has not yet been fully elucidated. But it is currently known that the disruption of Wnt signaling triggered by chronic hyperglycemia is involved in the pathogenesis of diabetic osteoporosis. There are two main types of Wnt signaling pathways, the canonical Wnt signaling pathway (β-catenin-dependent) and the non-canonical Wnt signaling pathway (non-β-catenin-dependent), both of which play an important role in regulating the balance between bone formation and bone resorption. Therefore, this review systematically describes the effects of abnormal Wnt pathway signaling on bone homeostasis under hyperglycemia, hoping to reveal the relationship between Wnt signaling and diabetic osteoporosis to further improve understanding of this disease.
Collapse
Affiliation(s)
- Kairan Bao
- Department of Integrated Traditional & Western Medicine, Affiliated hospital of North, China University of Science and Technology, Jianshe South Road 73, Tangshan, 063000, Hebei, People's Republic of China.
| | - Yinghua Jiao
- Department of Integrated Traditional & Western Medicine, Affiliated hospital of North, China University of Science and Technology, Jianshe South Road 73, Tangshan, 063000, Hebei, People's Republic of China
- North China University of Science and Technology, Bohai Road 21, Caofeidian Dis, Tangshan, 063210, Hebei, People's Republic of China
| | - Lei Xing
- Department of Integrated Traditional & Western Medicine, Affiliated hospital of North, China University of Science and Technology, Jianshe South Road 73, Tangshan, 063000, Hebei, People's Republic of China
| | - Fang Zhang
- Department of Integrated Traditional & Western Medicine, Affiliated hospital of North, China University of Science and Technology, Jianshe South Road 73, Tangshan, 063000, Hebei, People's Republic of China
| | - Faming Tian
- Department of Integrated Traditional & Western Medicine, Affiliated hospital of North, China University of Science and Technology, Jianshe South Road 73, Tangshan, 063000, Hebei, People's Republic of China
- North China University of Science and Technology, Bohai Road 21, Caofeidian Dis, Tangshan, 063210, Hebei, People's Republic of China
| |
Collapse
|
|
8
|
Riddle RC. Endocrine Functions of Sclerostin. CURRENT OPINION IN ENDOCRINE AND METABOLIC RESEARCH 2023; 28:10.1016/j.coemr.2022.100433. [PMID: 36713826 PMCID: PMC9881182 DOI: 10.1016/j.coemr.2022.100433] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Sclerostin, the product of the SOST gene has primarily been studied for its profound impact on bone mass. By interacting with LRP5 and LRP6, the glycoprotein suppresses the propagation of Wnt signals to β-catenin and thereby suppresses new bone formation. In this review, we discuss emerging data which suggest that sclerostin also acts outside the skeleton to influence metabolism. In humans, serum sclerostin levels are associated with body mass index and indices of metabolic function. Likewise, genetic mouse models of Sost gene deficiency indicate sclerostin influences adipocyte development and insulin signaling. These data raise the possibility that sclerostin neutralization may be effective at treating two epidemic conditions: osteoporosis and obesity.
Collapse
Affiliation(s)
- Ryan C. Riddle
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland, USA.,Research and Development Service, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA.,Address Correspondence to: Ryan C. Riddle, Ph.D., Department of Orthopaedics, University of Maryland School of Medicine, 660 W. Redwood Street, Room 592, Baltimore, MD 21201, USA, , Ph: 410-706-0422
| |
Collapse
|
|
9
|
Walle M, Whittier DE, Frost M, Müller R, Collins CJ. Meta-analysis of Diabetes Mellitus-Associated Differences in Bone Structure Assessed by High-Resolution Peripheral Quantitative Computed Tomography. Curr Osteoporos Rep 2022; 20:398-409. [PMID: 36190648 PMCID: PMC9718715 DOI: 10.1007/s11914-022-00755-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/26/2022] [Indexed: 01/30/2023]
Abstract
PURPOSE OF REVIEW Diabetes mellitus is defined by elevated blood glucose levels caused by changes in glucose metabolism and, according to its pathogenesis, is classified into type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. Diabetes mellitus is associated with multiple degenerative processes, including structural alterations of the bone and increased fracture risk. High-resolution peripheral computed tomography (HR-pQCT) is a clinically applicable, volumetric imaging technique that unveils bone microarchitecture in vivo. Numerous studies have used HR-pQCT to assess volumetric bone mineral density and microarchitecture in patients with diabetes, including characteristics of trabecular (e.g. number, thickness and separation) and cortical bone (e.g. thickness and porosity). However, study results are heterogeneous given different imaging regions and diverse patient cohorts. RECENT FINDINGS This meta-analysis assessed T1DM- and T2DM-associated characteristics of bone microarchitecture measured in human populations in vivo reported in PubMed- and Embase-listed publications from inception (2005) to November 2021. The final dataset contained twelve studies with 516 participants with T2DM and 3067 controls and four studies with 227 participants with T1DM and 405 controls. While T1DM was associated with adverse trabecular characteristics, T2DM was primarily associated with adverse cortical characteristics. These adverse effects were more severe at the radius than the load-bearing tibia, indicating increased mechanical loading may compensate for deleterious bone microarchitecture changes and supporting mechanoregulation of bone fragility in diabetes mellitus. Our meta-analysis revealed distinct predilection sites of bone structure aberrations in T1DM and T2DM, which provide a foundation for the development of animal models of skeletal fragility in diabetes and may explain the uncertainty of predicting bone fragility in diabetic patients using current clinical algorithms.
Collapse
Affiliation(s)
- Matthias Walle
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | | | - Morten Frost
- Molecular Endocrinology Laboratory & Steno Diabetes Centre, Odense University Hospital, University of Southern Denmark, Odense, Denmark
| | - Ralph Müller
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Caitlyn J Collins
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland.
- Department of Biomedical Engineering and Mechanics, Virginia Tech, 323 Kelly Hall, 325 Stanger Street, Blacksburg, 24061, VA, USA.
| |
Collapse
|
|
10
|
Abstract
PURPOSE OF REVIEW Better understanding of the mechanisms underlying skeletal dysfunction in the context of diabetes is needed to guide the development of therapeutic interventions to reduce the burden of diabetic fractures. Osteocytes, the 'master regulators' of bone remodeling, have emerged as key culprits in the pathogenesis of diabetes-related skeletal fragility. RECENT FINDINGS Both type 1 diabetes and type 2 diabetes cause chronic hyperglycemia that, over time, reduces bone quality and bone formation. In addition to acting as mechanosensors, osteocytes are important regulators of osteoblast and osteoclast activities; however, diabetes leads to osteocyte dysfunction. Indeed, diabetes causes the accumulation of advanced glycation end-products and senescent cells that can affect osteocyte viability and functions via increased receptor for advanced glycation endproducts (RAGE) signaling or the production of a pro-inflammatory senescence-associated secretory phenotype. These changes may increase osteocyte-derived sclerostin production and decrease the ability of osteocytes to sense mechanical stimuli thereby contributing to poor bone quality in humans with diabetes. SUMMARY Osteocyte dysfunction exists at the nexus of diabetic skeletal disease. Therefore, interventions targeting the RAGE signaling pathway, senescent cells, and those that inhibit sclerostin or mechanically stimulate osteocytes may alleviate the deleterious effects of diabetes on osteocytes and bone quality.
Collapse
Affiliation(s)
| | | | - Joshua N. Farr
- Correspondence: Joshua N. Farr, , Mayo Clinic, Guggenheim 7-11D, 200 First Street SW, Rochester, MN 55905, Telephone: 507-538-0085
| |
Collapse
|
|
11
|
Zhu M, Fan Z. The role of the Wnt signalling pathway in the energy metabolism of bone remodelling. Cell Prolif 2022; 55:e13309. [PMID: 35811348 DOI: 10.1111/cpr.13309] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/07/2022] [Accepted: 06/24/2022] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVES Bone remodelling is necessary to repair old and impaired bone caused by aging and its effects. Injury in the process of bone remodelling generally leads to the development of various bone diseases. Energy metabolism plays crucial roles in bone cell formation and function, the disorder of which will disrupt the balance between bone formation and bone resorption. MATERIALS AND METHODS Here, we review the intrinsic interactions between bone remodelling and energy metabolism and the role of the Wnt signalling pathway. RESULTS We found a close interplay between metabolic pathways and bone homeostasis, demonstrating that bone plays an important role in the regulation of energy balance. We also discovered that Wnt signalling is associated with multiple biological processes regulating energy metabolism in bone cells. CONCLUSIONS Thus, targeted regulation of Wnt signalling and the recovery of the energy metabolism function of bone cells are key means for the treatment of metabolic bone diseases.
Collapse
Affiliation(s)
- Mengyuan Zhu
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.,Research Unit of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhipeng Fan
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.,Research Unit of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| |
Collapse
|
|
12
|
Kurban S, Selver Eklioglu B, Selver MB. Investigation of the relationship between serum sclerostin and dickkopf-1 protein levels with bone turnover in children and adolescents with type-1 diabetes mellitus. J Pediatr Endocrinol Metab 2022; 35:673-679. [PMID: 35411762 DOI: 10.1515/jpem-2022-0001] [Citation(s) in RCA: 3] [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: 01/01/2022] [Accepted: 03/15/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Diabetes mellitus (DM) is widely known to have a detrimental effect on bone health and is associated with increased fracture risk. Recently, the Wnt/beta-catenin signaling pathway and its inhibitors sclerostin and dickkopf-1 (Dkk-1) were found to be involved in the control of bone mass. The present study aimed to measure serum sclerostin and Dkk-1 protein levels in children and adolescents with type-1 DM and compare with other bone turnover markers and bone mineral density (BMD). METHODS This study was performed on 40 children and adolescents with type-I DM and 40 healthy children and adolescents. Anthropometric measurements and pubertal examination were done. In addition to laboratory analysis, dickkopf-1, sclerostin, cross-linked N-telopeptides of type I collagen (NTx), bone alkaline phosphatase (bALP), and osteocalcin levels were studied. BMD of the participants was measured by calcaneus ultrasonography. RESULTS Dickkopf-1 levels of the children and adolescents with type-1 DM were significantly higher, vitamin D, NTx, osteocalcin, and phosphorus levels were significantly lower than those of the controls (p<0.001). Fasting blood glucose, HbA1c, and insulin were significantly higher in the type 1 DM group (p<0.01). CONCLUSIONS Both bone remodeling and its compensatory mechanism bone loss are lower in children and adolescents with type-1 DM than in the controls. Also, higher levels of Dkk-1 play a role in decreased bone turnover in these patients. Since Dkk-1 and sclerostin seem to take a role in treating metabolic bone diseases in the future, we believe that our findings are significant in this respective.
Collapse
Affiliation(s)
- Sevil Kurban
- Department of Biochemistry, Necmettin Erbakan University Faculty of Medicine, Konya, Turkey
| | - Beray Selver Eklioglu
- Division of Pediatric Endocrinology, Necmettin Erbakan University Faculty of Medicine, Konya, Turkey
| | - Muhammed Burak Selver
- Department of Pediatrics, Necmettin Erbakan University Faculty of Medicine, Konya, Turkey
- Istanbul University, Institute of Health Sciences and Institute of Child Health Social Pediatrics PhD Program, Istanbul, Turkey
| |
Collapse
|
|
13
|
Rubin MR, de Boer IH, Backlund JYC, Arends V, Gubitosi-Klug R, Wallia A, Sinha Gregory N, Barnie A, Burghardt AJ, Lachin JM, Braffett BH, Schwartz AV. Biochemical Markers of Bone Turnover in Older Adults With Type 1 Diabetes. J Clin Endocrinol Metab 2022; 107:e2405-e2416. [PMID: 35188961 PMCID: PMC9113800 DOI: 10.1210/clinem/dgac099] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Type 1 diabetes (T1D) is characterized by high fracture risk, yet little is known regarding diabetes-related mechanisms or risk factors. OBJECTIVE Determine whether glycemic control, advanced glycation end products (AGEs), and microvascular complications are associated with bone turnover markers among older T1D adults. DESIGN Cross-sectional. SETTING Epidemiology of Diabetes Interventions and Complications study (6 of 27 clinical centers). PARTICIPANTS 232 T1D participants followed for >30 years. EXPOSURES Glycemic control ascertained as concurrent and cumulative hemoglobin A1c (HbA1c); kidney function, by estimated glomerular filtration rates (eGFR); and AGEs, by skin intrinsic fluorescence. MAIN OUTCOME MEASURES Serum procollagen 1 intact N-terminal propeptide (PINP), bone-specific alkaline phosphatase (bone ALP), serum C-telopeptide (sCTX), tartrate-resistant acid phosphatase 5b (TRACP5b), and sclerostin. RESULTS Mean age was 59.6 ± 6.8 years, and 48% were female. In models with HbA1c, eGFR, and AGEs, adjusted for age and sex, higher concurrent HbA1c was associated with lower PINP [β -3.4 pg/mL (95% CI -6.1, -0.7), P = 0.015 for each 1% higher HbA1c]. Lower eGFR was associated with higher PINP [6.9 pg/mL (95% CI 3.8, 10.0), P < 0.0001 for each -20 mL/min/1.73 m2 eGFR], bone ALP [1.0 U/L (95% CI 0.2, 1.9), P = 0.011], sCTX [53.6 pg/mL (95% CI 32.6, 74.6), P < 0.0001], and TRACP5b [0.3 U/L (95% CI 0.1, 0.4), P = 0.002]. However, AGEs were not associated with any bone turnover markers in adjusted models. HbA1c, eGFR, and AGEs were not associated with sclerostin levels. CONCLUSIONS Among older adults with T1D, poor glycemic control is a risk factor for reduced bone formation, while reduced kidney function is a risk factor for increased bone resorption and formation.
Collapse
Affiliation(s)
| | - Ian H de Boer
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Jye-Yu C Backlund
- The Biostatistics Center, George Washington University, Rockville, MD,USA
| | - Valerie Arends
- Departement of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Rose Gubitosi-Klug
- Case Western Reserve/Rainbow Babies and Children’s Hospital, Cleveland, OH, USA
| | - Amisha Wallia
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | | | | | - Andrew J Burghardt
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA
| | - John M Lachin
- The Biostatistics Center, George Washington University, Rockville, MD,USA
| | - Barbara H Braffett
- The Biostatistics Center, George Washington University, Rockville, MD,USA
| | - Ann V Schwartz
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
| |
Collapse
|
|
14
|
Yu S, Li D, Zhang N, Ni S, Sun M, Wang L, Xiao H, Liu D, Liu J, Yu Y, Zhang Z, Yeung STY, Zhang S, Lu A, Zhang Z, Zhang B, Zhang G. Drug discovery of sclerostin inhibitors. Acta Pharm Sin B 2022; 12:2150-2170. [PMID: 35646527 PMCID: PMC9136615 DOI: 10.1016/j.apsb.2022.01.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/03/2021] [Accepted: 12/16/2021] [Indexed: 12/18/2022] Open
Abstract
Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA, the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis; however, it conferred high cardiovascular risk in clinical trials. Furthermore, romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.
Collapse
|
|
15
|
Coll JC, Garceau É, Leslie WD, Genest M, Michou L, Weisnagel SJ, Mac-Way F, Albert C, Morin SN, Rabasa-Lhoret R, Gagnon C. Prevalence of Vertebral Fractures in Adults With Type 1 Diabetes: DenSiFy Study (Diabetes Spine Fractures). J Clin Endocrinol Metab 2022; 107:e1860-e1870. [PMID: 35090169 DOI: 10.1210/clinem/dgac031] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Vertebral fracture (VF) prevalence up to 24% has been reported among young people with type 1 diabetes (T1D). If this high prevalence is confirmed, individuals with T1D could benefit from preventative VF screening. OBJECTIVE We compared the prevalence of VFs between adults with T1D and nondiabetic controls. METHODS This cross-sectional study included 127 adults with T1D, and 65 controls with a similar age, sex, and BMI distribution, from outpatient clinics of 2 tertiary care centers. Vertebral fracture assessment (VFA) by dual-energy x-ray absorptiometry (DXA) was used for prevalent VFs. The modified algorithm-based qualitative (mABQ) method was applied. Bone mineral density (BMD) and trabecular bone score (TBS) were assessed by DXA. Serum bone turnover markers and sclerostin were measured in a subgroup of participants. RESULTS Participants with T1D (70 women, 57 men) had a mean age of 42.8 ± 14.8 years, median diabetes duration of 25.8 (15.8-34.4) years, mean BMI of 26.6 ± 5.4 kg/m2 and mean HbA1c over the past 3 years of 7.5 ± 0.9%. Controls (35 women, 30 men) had mean age of 42.2 ± 15.9 years and mean BMI of 26.1 ± 5.1 kg/m2. VF prevalence was comparable between groups (2.4% vs 3.1%, P = 0.99). TBS, BMD at the total hip and femoral neck, and bone formation and resorption markers were lower while sclerostin levels were similar in participants with T1D vs controls. CONCLUSION Our VFA results using the mABQ method do not confirm increased prevalence of VFs in men and women with relatively well-controlled T1D.
Collapse
Affiliation(s)
| | - Élodie Garceau
- Centre de recherche, CHU de Québec-Université Laval, Quebec City, QC, Canada
| | - William D Leslie
- Department of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Mathieu Genest
- Centre de recherche, CHU de Québec-Université Laval, Quebec City, QC, Canada
| | - Laëtitia Michou
- Centre de recherche, CHU de Québec-Université Laval, Quebec City, QC, Canada
- Department of Medicine, Université Laval, Quebec City, QC, Canada
| | - S John Weisnagel
- Centre de recherche, CHU de Québec-Université Laval, Quebec City, QC, Canada
- Department of Medicine, Université Laval, Quebec City, QC, Canada
| | - Fabrice Mac-Way
- Centre de recherche, CHU de Québec-Université Laval, Quebec City, QC, Canada
- Department of Medicine, Université Laval, Quebec City, QC, Canada
| | - Caroline Albert
- Centre hospitalier de l'Université de Montréal, Montreal, QC, Canada
| | - Suzanne N Morin
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | | | - Claudia Gagnon
- Centre de recherche, CHU de Québec-Université Laval, Quebec City, QC, Canada
- Department of Medicine, Université Laval, Quebec City, QC, Canada
| |
Collapse
|
|
16
|
Jürimäe J, Karvelyte V, Remmel L, Tamm AL, Purge P, Gruodyte-Raciene R, Kamandulis S, Maasalu K, Gracia-Marco L, Tillmann V. Serum sclerostin concentration is associated with specific adipose, muscle and bone tissue markers in lean adolescent females with increased physical activity. J Pediatr Endocrinol Metab 2021; 34:755-761. [PMID: 33851796 DOI: 10.1515/jpem-2020-0662] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 02/12/2021] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Sclerostin is an important regulator of bone mass involving the Wnt/β-catenin signalling pathway. Relatively few studies have investigated the relationships of circulating sclerostin levels with adiposity-related and muscle-related biochemical factors in individuals with increased energy metabolism. The aim of this study was to investigate the associations of circulating sclerostin with adipokines, myokines, osteokines and body composition values in lean adolescent females with increased physical activity. METHODS A total of 73 adolescent females who were physically active and aged 14-18 years old participated in the study. Sclerostin, leptin, resistin, tumour necrosis factor (TNF)-α, interleukin (IL)-6, irisin, osteocalcin, C-terminal telopeptide of type I collagen (CTx), insulin-like growth factor (IGF)-1 and insulin were obtained from fasting blood samples. Body composition was measured by dual-energy X-ray absorptiometry (DXA) and analyzed for body fat mass, lean body mass, bone mineral content and muscle mass. RESULTS Serum sclerostin (117.9 ± 60.3 pg/mL) was correlated with age, age at menarche, body fat, muscle mass, training activity, leptin, TNF-α, irisin, osteocalcin, CTx and IGF-1. Multivariate linear regression analysis demonstrated that fat mass (β = 0.434; p = 0.001), leptin (β = -0.308; p = 0.015), irisin (β = 0.227; p = 0.024) and CTx (β = 0.290; p = 0.031) were the most important predictors of serum sclerostin concentration. CONCLUSIONS Bone-derived sclerostin is associated with specific adipokine, myokine and osteokine values in lean adolescent females with increased physical activity. These results suggest that the interactions between bone, adipose and muscle tissues could also be associated with circulating sclerostin concentrations.
Collapse
Affiliation(s)
- Jaak Jürimäe
- Institute of Sport Sciences and Physiotherapy, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | | | - Liina Remmel
- Institute of Sport Sciences and Physiotherapy, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | | | - Priit Purge
- Institute of Sport Sciences and Physiotherapy, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | | | | | - Katre Maasalu
- Institute of Clinical Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | - Luis Gracia-Marco
- PROFITH (PROmoting FITness and Health through physical activity) Research Group, Department of Physical Education and Sports, Faculty of Sport Sciences, Sport and Health University Research Institute (iMUDS), University of Granada, Granada, Spain
| | - Vallo Tillmann
- Institute of Clinical Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia
| |
Collapse
|
|
17
|
Schacter GI, Leslie WD. Diabetes and Osteoporosis: Part I, Epidemiology and Pathophysiology. Endocrinol Metab Clin North Am 2021; 50:275-285. [PMID: 34023043 DOI: 10.1016/j.ecl.2021.03.005] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Both diabetes and osteoporosis are increasingly prevalent diseases, in part owing to aging populations worldwide. Epidemiologic data have shown that other organs may be adversely affected by diabetes, including the skeleton, in what has become known as diabetes-induced osteoporosis, which represents the combined impact of conventional osteoporosis with the additional fracture burden attributed to diabetes. There is an increased risk of fracture in patients with Type 1 and Type 2 diabetes, and some antidiabetic medications also may contribute to increased risk of fracture in diabetes.
Collapse
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.
| |
Collapse
|
|
18
|
Dixit M, Liu Z, Poudel SB, Yildirim G, Zhang YZ, Mehta S, Murik O, Altarescu G, Kobayashi Y, Shimizu E, Schaffler MB, Yakar S. Skeletal Response to Insulin in the Naturally Occurring Type 1 Diabetes Mellitus Mouse Model. JBMR Plus 2021; 5:e10483. [PMID: 33977201 PMCID: PMC8101621 DOI: 10.1002/jbm4.10483] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/03/2021] [Accepted: 02/24/2021] [Indexed: 11/24/2022] Open
Abstract
Patients with type 1 diabetes mellitus (T1DM) exhibit reduced BMD and significant increases in fracture risk. Changes in BMD are attributed to blunted osteoblast activity and inhibited bone remodeling, but these cannot fully explain the impaired bone integrity in T1DM. The goal of this study was to determine the cellular mechanisms that contribute to impaired bone morphology and composition in T1DM. Nonobese diabetic (NOD) mice were used, along with μCT, histomorphometry, histology, Raman spectroscopy, and RNAseq analyses of several skeletal sites in response to naturally occurring hyperglycemia and insulin treatment. The bone volume in the axial skeleton was found to be severely reduced in diabetic NOD mice and was not completely resolved with insulin treatment. Decreased bone volume in diabetic mice was associated with increased sclerostin expression in osteocytes and attenuation of bone formation indices without changes in bone resorption. In the face of blunted bone remodeling, decreases in the mineral:matrix ratio were found in cortical bones of diabetic mice by Raman microspectroscopy, suggesting that T1DM did not affect the bone mineralization process per se, but rather resulted in microenvironmental alterations that favored mineral loss. Bone transcriptome analysis indicated metabolic shifts in response to T1DM. Dysregulation of genes involved in fatty acid oxidation, transport, and synthesis was found in diabetic NOD mice. Specifically, pyruvate dehydrogenase kinase isoenzyme 4 and glucose transporter 1 levels were increased, whereas phosphorylated-AKT levels were significantly reduced in diabetic NOD mice. In conclusion, in addition to the blunted bone formation, osteoblasts and osteocytes undergo metabolic shifts in response to T1DM that may alter the microenvironment and contribute to mineral loss from the bone matrix. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Collapse
Affiliation(s)
- Manisha Dixit
- David B. Kriser Dental Center, Department of Molecular PathobiologyNew York University College of Dentistry New YorkNew YorkNYUSA
| | - Zhongbo Liu
- David B. Kriser Dental Center, Department of Molecular PathobiologyNew York University College of Dentistry New YorkNew YorkNYUSA
| | - Sher Bahadur Poudel
- David B. Kriser Dental Center, Department of Molecular PathobiologyNew York University College of Dentistry New YorkNew YorkNYUSA
| | - Gozde Yildirim
- David B. Kriser Dental Center, Department of Molecular PathobiologyNew York University College of Dentistry New YorkNew YorkNYUSA
| | - Yanjiao Zhang Zhang
- David B. Kriser Dental Center, Department of Molecular PathobiologyNew York University College of Dentistry New YorkNew YorkNYUSA
| | - Shilpa Mehta
- David B. Kriser Dental Center, Department of Molecular PathobiologyNew York University College of Dentistry New YorkNew YorkNYUSA
| | - Omer Murik
- Medical Genetics Institute, Shaare Zedek Medical CenterJerusalemIsrael
| | - Geona Altarescu
- Medical Genetics Institute, Shaare Zedek Medical CenterJerusalemIsrael
| | | | - Emi Shimizu
- Oral Biology DepartmentRutgers School of Dental MedicineNewarkNJUSA
| | | | - Shoshana Yakar
- David B. Kriser Dental Center, Department of Molecular PathobiologyNew York University College of Dentistry New YorkNew YorkNYUSA
| |
Collapse
|
|
19
|
Lauterlein JJL, Hermann P, Konrad T, Wolf P, Nilsson P, Sánchez RG, Ferrannini E, Balkau B, Højlund K, Frost M. Serum sclerostin and glucose homeostasis: No association in healthy men. Cross-sectional and prospective data from the EGIR-RISC study. Bone 2021; 143:115681. [PMID: 33035729 DOI: 10.1016/j.bone.2020.115681] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 10/04/2020] [Accepted: 10/05/2020] [Indexed: 01/24/2023]
Abstract
INTRODUCTION Sclerostin, an inhibitor of bone formation, has emerged as a potential negative regulator of glucose homeostasis. We aimed to investigate if serum sclerostin associates with insulin sensitivity, beta cell function, prediabetes or metabolic syndrome in healthy men. MATERIALS AND METHODS Serum sclerostin was measured in basal and insulin-stimulated samples from 526 men without diabetes from the RISC cohort study. An OGTT was performed at baseline and after 3 years. An IVGTT and a hyperinsulinaemic-euglycaemic clamp were performed at baseline. Insulin sensitivity was estimated by the oral glucose sensitivity index (OGIS) and the M-value relative to insulin levels. Beta cell function was assessed by the acute and total insulin secretion (ISRtot) and by beta cell glucose sensitivity. RESULTS Serum sclerostin levels correlated positively with age but were similar in individuals with (n = 69) and without (n = 457) prediabetes or the metabolic syndrome. Serum sclerostin was associated with measures of neither insulin sensitivity nor beta cell function at baseline in age-adjusted analyses including all participants. However, baseline serum sclerostin correlated inversely with OGIS at follow-up in men without prediabetes (B: -0.29 (-0.57, -0.01) p = 0.045), and inversely with beta cell glucose sensitivity in men with prediabetes (B: -13.3 (-26.3, -0.2) p = 0.046). Associations between serum sclerostin and 3-year changes in measures of glucose homeostasis were not observed. Acute hyperinsulinemia suppressed serum sclerostin (p = 0.02), and this reduction correlated with OGIS and ISRtot. CONCLUSIONS Overall, serum sclerostin was not associated with prediabetes, insulin sensitivity or insulin secretion in healthy men. The inverse relationship between serum sclerostin and insulin sensitivity at follow-up was weak and likely not of clinical relevance. The ability of insulin to reduce sclerostin, possibly promoting bone formation, needs to be clarified.
Collapse
Affiliation(s)
| | - Pernille Hermann
- Department of Endocrinology, Odense University Hospital, Odense, Denmark
| | - Thomas Konrad
- Institute for Metabolic Research, Goethe University, Frankfurt am Main, Germany
| | - Peter Wolf
- Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Peter Nilsson
- Department of Clinical Sciences, Clinical Research Center, Lund University, Malmö, Sweden; Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden
| | | | | | - Beverley Balkau
- Clinical Epidemiology, Université Paris-Saclay, UVSQ, Inserm, CESP, 94807 Villejuif, France
| | - Kurt Højlund
- Steno Diabetes Centre Odense, Odense University Hospital, Odense, Denmark
| | - Morten Frost
- Department of Endocrinology, Odense University Hospital, Odense, Denmark; Steno Diabetes Centre Odense, Odense University Hospital, Odense, Denmark
| |
Collapse
|
|
20
|
Plasma sclerostin levels are associated with nutritional status and insulin resistance but not hormonal disturbances in women with polycystic ovary syndrome. Arch Gynecol Obstet 2020; 302:1025-1031. [PMID: 32592042 PMCID: PMC7471162 DOI: 10.1007/s00404-020-05656-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 06/18/2020] [Indexed: 12/18/2022]
Abstract
Objective The aim of this study was to evaluate the circulating sclerostin levels with nutritional status, insulin resistance and hormonal disturbances in women with polycystic ovary syndrome (PCOS). Patients and methods The cross-sectional study involved 98 PCOS inpatients (20 normal weight, 17 overweight and 61 obese) with stable body mass. Body composition was assessed by bioimpedance method in addition to anthropometric measurements (body mass and height). Serum/plasma concentrations of glucose, insulin (with the calculation of homeostatic model assessment insulin resistance—HOMA-IR), estradiol, total testosterone, sex hormone-binding globulin (SHBG) and sclerostin were measured. Free androgen index (FAI) and estradiol/testosterone index were calculated. Results Plasma sclerostin levels were significantly higher in obese [0.61 (interquartile range 0.53–0.77) ng/mL] than in overweight [0.53 (0.49–0.57) ng/mL] and normal weight [0.49 (0.42–0.54) ng/mL] groups. Plasma sclerostin levels were significantly higher in the subgroup with insulin resistance [0.65 (interquartile range 0.53–0.77) vs. 0.52 (0.46–0.58) ng/mL; p < 0.001], while similar concentrations were observed in subgroups with FAI below and above median. Plasma sclerostin levels variability were explained by BMI (r = 0.40), the percentage of body fat (r = 0.40) and HOMA-IR values (r = 0.34) in multivariable models. Conclusions Circulating sclerostin levels in women with PCOS are related to nutritional status and insulin resistance, but not to sex hormone disturbances.
Collapse
|
|
21
|
Serum Sclerostin, Body Composition, and Sarcopenia in Hemodialysis Patients with Diabetes. Int J Nephrol 2020; 2020:4596920. [PMID: 32095286 PMCID: PMC7035555 DOI: 10.1155/2020/4596920] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 01/02/2020] [Accepted: 01/08/2020] [Indexed: 12/19/2022] Open
Abstract
Sclerostin (Scl) is an osteoblast-inhibiting glycoprotein that is secreted mainly by osteocytes and is regulated by hormonal changes and skeletal loading. Decreased physical function and high serum Scl concentrations have been reported in chronic renal failure patients but little is known to date about the differences between diabetic and non-diabetic patients on hemodialysis who are susceptible to both sarcopenia and bone fragility. Objective.To determine the prevalence of sarcopenia and its association with serum Scl concentrations and metabolic parameters in 92 patients on hemodialysis. Anthropometric data and physical performance were evaluated in this study. Blood samples were collected for Scl, glucose, cholesterol, triglycerides, calcium, phosphate, PTH, and 25 OH-vitamin D measurements. Lean mass was evaluated using multifrequency electro-bioimpedance after dialysis session. Results. Mean age was 63.3 ± 13.6 years, 63% of patients were male, and 44.6% had diabetes. Mean body mass index (BMI) was higher in diabetics (26.6 ± 5.2 vs. 24.1 ± 3.7; p=0.01) and there were no differences in gait speed and handgrip strength between diabetic and non-diabetic subjects. A low skeletal muscle mass index (SMI) was identified in 65.2% of the participants, and among them 76.7% were men and 36.7% were diabetics. Mean serum Scl was 86.9 ± 39.0 pmol/L, which was higher in men (94.6 ± 41.7; p=0.017), in those individuals with low SMI (94.9 ± 40.7; p < 0.001), and in diabetics (97.2 ± 46.6; p < 0.003). After multivariate analysis and adjustments for potential confounders, high serum Scl was independently associated with low SMI and with the presence of diabetes. The following variables correlated positively with diabetes: blood pressure; BMI; waist circumference; waist/hip ratio; plasma glucose; serum Scl; and fat mass. Conclusions. We found higher serum Scl concentrations in hemodialysis patients with diabetes and these were inversely related to muscle mass.
Collapse
|
|
22
|
Xu Y, Gao C, He J, Gu W, Yi C, Chen B, Wang Q, Tang F, Xu J, Yue H, Zhang Z. Sclerostin and Its Associations With Bone Metabolism Markers and Sex Hormones in Healthy Community-Dwelling Elderly Individuals and Adolescents. Front Cell Dev Biol 2020; 8:57. [PMID: 32117983 PMCID: PMC7020200 DOI: 10.3389/fcell.2020.00057] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 01/22/2020] [Indexed: 12/22/2022] Open
Abstract
Sclerostin is an important regulator of bone mass involving Wnt/β-catenin signaling pathway. We aimed to obtain the profile of serum sclerostin level and explore its associations with bone metabolism markers and sex hormones in healthy community-dwelling Chinese elderly individuals and adolescents. A cross-sectional study was performed in three communities in Shanghai. In all, 861 participants, including 574 healthy elderly individuals, and 287 healthy adolescents, were recruited. The levels of serum sclerostin, procollagen type 1 N-terminal propeptide (P1NP), β-CrossLaps of type I collagen containing cross-linked C-telopeptide (β-CTX), parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], estradiol (E2), testosterone (T), and sex hormone-binding globulin (SHBG) were measured in blood samples from all participants. Median sclerostin level was higher in males than in females and in elderly individuals than in adolescents (elderly males: 54.89 pmol/L, elderly females: 39.95 pmol/L, adolescent males: 36.58 pmol/L, adolescent females: 27.06 pmol/L; both P < 0.05). In elderly individuals, serum sclerostin was positively correlated with age (β = 0.176, P < 0.001) and T (β = 0.248, P = 0.001), but negatively associated to P1NP (β = −0.140, P = 0.001). In adolescents, circulating sclerostin was significantly and positively associated with P1NP (β = 0.192, P = 0.003). The directions of the association between sclerostin and P1NP were opposite in Chinese elderly individuals and adolescents, which may reflect that sclerostin plays distinct roles in different functional states of the skeleton. Our findings revealed the rough profile of circulating sclerostin level in general healthy Chinese population and its associations with bone metabolism markers and sex hormones, which may provide a clue to further elucidate the cross action of sclerostin in bone metabolism and sexual development.
Collapse
Affiliation(s)
- Yang Xu
- Shanghai Clinical Research Center of Bone Disease, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Chao Gao
- Shanghai Clinical Research Center of Bone Disease, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jinwei He
- Shanghai Clinical Research Center of Bone Disease, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wenqin Gu
- Fenglin Community Health Service Center, Shanghai, China
| | - Chuntao Yi
- Fenglin Community Health Service Center, Shanghai, China
| | - Bihua Chen
- Longhua Community Health Service Center, Shanghai, China
| | - Qingqing Wang
- Longhua Community Health Service Center, Shanghai, China
| | - Feng Tang
- Qixian Community Health Service Center, Shanghai, China
| | - Juliang Xu
- Qixian Community Health Service Center, Shanghai, China
| | - Hua Yue
- Shanghai Clinical Research Center of Bone Disease, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zhenlin Zhang
- Shanghai Clinical Research Center of Bone Disease, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| |
Collapse
|
|
23
|
Eller-Vainicher C, Cairoli E, Grassi G, Grassi F, Catalano A, Merlotti D, Falchetti A, Gaudio A, Chiodini I, Gennari L. Pathophysiology and Management of Type 2 Diabetes Mellitus Bone Fragility. J Diabetes Res 2020; 2020:7608964. [PMID: 32566682 PMCID: PMC7262667 DOI: 10.1155/2020/7608964] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 04/29/2020] [Accepted: 05/04/2020] [Indexed: 12/14/2022] Open
Abstract
Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of bone fragility fractures compared to nondiabetic subjects. This increased fracture risk may occur despite normal or even increased values of bone mineral density (BMD), and poor bone quality is suggested to contribute to skeletal fragility in this population. These concepts explain why the only evaluation of BMD could not be considered an adequate tool for evaluating the risk of fracture in the individual T2DM patient. Unfortunately, nowadays, the bone quality could not be reliably evaluated in the routine clinical practice. On the other hand, getting further insight on the pathogenesis of T2DM-related bone fragility could consent to ameliorate both the detection of the patients at risk for fracture and their appropriate treatment. The pathophysiological mechanisms underlying the increased risk of fragility fractures in a T2DM population are complex. Indeed, in T2DM, bone health is negatively affected by several factors, such as inflammatory cytokines, muscle-derived hormones, incretins, hydrogen sulfide (H2S) production and cortisol secretion, peripheral activation, and sensitivity. All these factors may alter bone formation and resorption, collagen formation, and bone marrow adiposity, ultimately leading to reduced bone strength. Additional factors such as hypoglycemia and the consequent increased propensity for falls and the direct effects on bone and mineral metabolism of certain antidiabetic medications may contribute to the increased fracture risk in this population. The purpose of this review is to summarize the literature evidence that faces the pathophysiological mechanisms underlying bone fragility in T2DM patients.
Collapse
Affiliation(s)
- C. Eller-Vainicher
- Unit of Endocrinology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - E. Cairoli
- Istituto Auxologico Italiano, IRCCS, Unit for Bone Metabolism Diseases and Diabetes & Lab of Endocrine and Metabolic Research, Italy
- Dept. of Clinical Sciences & Community Health, University of Milan, Milan, Italy
| | - G. Grassi
- Unit of Endocrinology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy
- Dept. of Clinical Sciences & Community Health, University of Milan, Milan, Italy
| | - F. Grassi
- Ramses Lab, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - A. Catalano
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - D. Merlotti
- Department of Medicine, Surgery and Neurosciences, University of Siena, Italy
| | - A. Falchetti
- Istituto Auxologico Italiano, IRCCS, Unit for Bone Metabolism Diseases and Diabetes & Lab of Endocrine and Metabolic Research, Italy
| | - A. Gaudio
- Department of Clinical and Experimental Medicine, University of Catania, University Hospital ‘G. Rodolico', Catania, Italy
| | - I. Chiodini
- Istituto Auxologico Italiano, IRCCS, Unit for Bone Metabolism Diseases and Diabetes & Lab of Endocrine and Metabolic Research, Italy
- Dept. of Clinical Sciences & Community Health, University of Milan, Milan, Italy
| | - L. Gennari
- Department of Medicine, Surgery and Neurosciences, University of Siena, Italy
| |
Collapse
|
|
24
|
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.
Collapse
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
| |
Collapse
|
|
25
|
Wędrychowicz A, Sztefko K, Starzyk JB. Sclerostin and its significance for children and adolescents with type 1 diabetes mellitus (T1D). Bone 2019; 120:387-392. [PMID: 30120991 DOI: 10.1016/j.bone.2018.08.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 07/05/2018] [Accepted: 08/07/2018] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Recent studies have shown that sclerostin, which is a negative regulator of bone formation, could play an important role in the crosstalk between bone and glucose metabolism. The role of sclerostin and its link with glucose homeostasis in type 1 diabetes mellitus (T1D) has not been yet studied extensively in children. The aim of this study was to assess sclerostin and its relationship between other bone and fat related factors as well as glucose metabolism in children and adolescents with T1D in comparison to their healthy peers. METHODS Forty patients with T1D, 18 girls, mean age 12.3 ± 4.7 yrs, and 28 healthy as controls (13.1 ± 4.2 yrs), sex and Tanner stage-matched were included into the study. Fasting blood samples for measurement of sclerostin, osteocalcin (OC), leptin, adiponectin, vitamin D, fasting glucose, lipid profile, HbA1c, and C-peptide were taken at 8.00 AM. RESULTS Sclerostin levels were significantly higher in patients with T1D than in the control group (p = 0.04) without significant differences between genders. Pearson correlation coefficients revealed a positive association between serum sclerostin levels and leptin OC (r = 0.59, p < 0.001) and a negative correlation between serum sclerostin levels and leptin (r = -0.32, p = 0.02) in all of the subjects and no significant correlations between sclerostin and adiponectin, 25(OH)D3, nor lipids. In the group of T1D patients a strong positive association between serum sclerostin levels and OC (r = 0.62, p < 0.001), and a negative association between serum sclerostin levels and HbA1c and leptin levels (r = -0.33, p = 0.04; r = -0.33, p = 0.03, respectively) were found. These associations were significant also after adjusting the analysis to the age, SDS-BMI and Tanner staging. In the healthy group after adjustment to age, SDS-BMI and Tanner stage, a negative correlation between sclerostin and C-peptide (r = -0.79, p = 0.02) was found. CONCLUSIONS Our data suggest a possible relationship between sclerostin and glucose metabolism in children and adolescents with T1D. It would be worth to investigate if an increase in sclerostin levels could present as a potential cause of the reduction of bone formation in T1D. Both bone-derived OC as well as fat-derived leptin seems to possibly modulate the participation of sclerostin in metabolic regulation in T1D.
Collapse
Affiliation(s)
- Anna Wędrychowicz
- Department of Pediatric and Adolescent Endocrinology, Pediatric Institute, Medical College, Jagiellonian University in Krakow, Poland.
| | - Krystyna Sztefko
- Department of Clinical Biochemistry, Pediatric Institute, Medical College, Jagiellonian University in Krakow, Poland
| | - Jerzy B Starzyk
- Department of Pediatric and Adolescent Endocrinology, Pediatric Institute, Medical College, Jagiellonian University in Krakow, Poland
| |
Collapse
|
|
26
|
Brunetti G, D'Amato G, Chiarito M, Tullo A, Colaianni G, Colucci S, Grano M, Faienza MF. An update on the role of RANKL-RANK/osteoprotegerin and WNT-ß-catenin signaling pathways in pediatric diseases. World J Pediatr 2019; 15:4-11. [PMID: 30343446 DOI: 10.1007/s12519-018-0198-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 10/04/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Bone remodeling is a lifelong process due to the balanced activity of osteoclasts (OCs), the bone-reabsorbing cells, and osteoblasts (OBs), and the bone-forming cells. This equilibrium is regulated by numerous cytokines, but it has been largely demonstrated that the RANK/RANKL/osteoprotegerin and Wnt/β-catenin pathways play a key role in the control of osteoclastogenesis and osteoblastogenesis, respectively. The pro-osteoblastogenic activity of the Wnt/β-catenin can be inhibited by sclerostin and Dickkopf-1 (DKK-1). RANKL, sclerostin and DKKs-1 are often up-regulated in bone diseases, and they are the target of new monoclonal antibodies. DATA SOURCES The authors performed a systematic literature search in PubMed and EMBASE to June 2018, reviewed and selected articles, based on pre-determined selection criteria. RESULTS We re-evaluated the role of RANKL, osteoprotegerin, sclerostin and DKK-1 in altered bone remodeling associated with some inherited and acquired pediatric diseases, such as type 1 diabetes mellitus (T1DM), alkaptonuria (AKU), hemophilia A, osteogenesis imperfecta (OI), 21-hydroxylase deficiency (21OH-D) and Prader-Willi syndrome (PWS). To do so, we considered recent clinical studies done on pediatric patients in which the roles of RANKL-RANK/osteoprotegerin and WNT-ß-catenin signaling pathways have been investigated, and for which innovative therapies for the treatment of osteopenia/osteoporosis are being developed. CONCLUSIONS The case studies taken into account for this review demonstrated that quite frequently both bone reabsorbing and bone deposition are impaired in pediatric diseases. Furthermore, for some of them, bone damage began in childhood but only manifested with age. The use of denosumab could represent a valid alternative therapeutic approach to improve bone health in children, although further studies need to be carried out.
Collapse
Affiliation(s)
- Giacomina Brunetti
- Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University "A. Moro" of Bari, Piazza G. Cesare 11, 70124, Bari, Italy
| | | | - Mariangela Chiarito
- Pediatric Section, Department of Biomedical Sciences and Human Oncology, University "A. Moro" of Bari, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Apollonia Tullo
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies-IBIOM, CNR, 70126, Bari, Italy
| | - Graziana Colaianni
- Department of Emergency and Organ Transplantation, University "A. Moro" of Bari, Bari, Italy
| | - Silvia Colucci
- Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University "A. Moro" of Bari, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Maria Grano
- Department of Emergency and Organ Transplantation, University "A. Moro" of Bari, Bari, Italy
| | - Maria Felicia Faienza
- Pediatric Section, Department of Biomedical Sciences and Human Oncology, University "A. Moro" of Bari, Piazza G. Cesare 11, 70124, Bari, Italy.
| |
Collapse
|
|
27
|
Kheniser KG, Polanco Santos CM, Kashyap SR. The effects of diabetes therapy on bone: A clinical perspective. J Diabetes Complications 2018; 32:713-719. [PMID: 29747995 DOI: 10.1016/j.jdiacomp.2018.04.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 03/21/2018] [Accepted: 04/14/2018] [Indexed: 12/16/2022]
Abstract
The effects of diabetes and diabetes therapy on bone are less known among clinicians. Traditionally, the emphasis of diabetes therapy has been on reducing cardiovascular risk by facilitating reductions in weight, blood pressure, blood sugar, systemic inflammation, and lipid levels. Now, with ample research demonstrating that patients with diabetes are more susceptible to bone fractures relative to controls, there has been a greater or renewed interest in studying the effects of diabetes therapy on bone. Interestingly, the majority of antidiabetic agents positively affect bone, but a few have detrimental effects. Specifically, although insulin has been demonstrated to be anabolic to bone, the rate of hypoglycemic episodes are increased with exogenous infusion; consequently, there is an increased fall and fracture frequency. Other agents such as thiazolidinediones have more direct negative effects on bone through transcriptional regulation. Even metabolic surgery, to a varying operation-dependent extent, exacerbates bone strength and may heighten fracture rate. The remaining diabetes agents seem to have neutral or positive effects on bone. With the increasing incidence of diabetes, it is more pertinent than ever to fully comprehend the effects of diabetes-related therapeutic modalities.
Collapse
MESH Headings
- Bone Density/drug effects
- Bone Diseases, Metabolic/etiology
- Bone Diseases, Metabolic/pathology
- Bone Diseases, Metabolic/prevention & control
- Bone and Bones/drug effects
- Bone and Bones/physiology
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/pathology
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/pathology
- Fractures, Bone/etiology
- Fractures, Bone/pathology
- Humans
- Hypoglycemic Agents/pharmacology
- Hypoglycemic Agents/therapeutic use
- Osteoporosis/etiology
- Osteoporosis/metabolism
- Osteoporosis/pathology
- Risk Factors
Collapse
Affiliation(s)
- Karim G Kheniser
- Department of Endocrinology and Metabolism, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, United States.
| | - Carmen M Polanco Santos
- Department of Endocrinology and Metabolism, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, United States.
| | - Sangeeta R Kashyap
- Department of Endocrinology and Metabolism, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, United States.
| |
Collapse
|
|
28
|
Franceschi R, Longhi S, Cauvin V, Fassio A, Gallo G, Lupi F, Reinstadler P, Fanolla A, Gatti D, Radetti G. Bone Geometry, Quality, and Bone Markers in Children with Type 1 Diabetes Mellitus. Calcif Tissue Int 2018; 102:657-665. [PMID: 29290007 DOI: 10.1007/s00223-017-0381-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 12/27/2017] [Indexed: 12/16/2022]
Abstract
Adults with Type 1 diabetes mellitus show a high risk of bone fracture, probably as a consequence of a decreased bone mass and microarchitectural bone alterations. The aim of the study was to investigate the potential negative effects of type 1 diabetes on bone geometry, quality, and bone markers in a group of children and adolescents. 96 children, mean age 10.5 ± 3.1 years, agreed to participate to the study. Bone geometry was evaluated on digitalized X-rays at the level of the 2nd metacarpal bone. The following parameters were investigated and expressed as SDS: outer diameter (D), inner diameter (d), cortical area (CA), and medullary area (MA). Bone strength was evaluated as Bending Breaking Resistance Index (BBRI) from the geometric data. Bone turnover markers (PINP, CTX-I, and BAP), sclerostin, Dkk-1, PTH, and 25OH-Vitamin D were also assessed. A group of healthy 40 subjects of normal body weight and height served as controls for the bone markers. D (- 0.99 ± 0.98), d (- 0.41 ± 0.88), CA (- 0.85 ± 0.78), and MA (- 0.46 ± 0.78) were all significantly smaller than in controls (p < 0.01). BBRI was significantly lower (- 2.61 ± 2.18; p < 0.0001). PTH, PINP, and BAP were higher in the diabetic children. Multiple regression analysis showed that CA and D were influenced by insulin/Kg/day and by BMI, while d was influenced by PINP only. Type 1 diabetic children show smaller and weaker bones. The increased bone turnover could play a key role since it might amplify the deficit in bone strength associated with the inadequate osteoblastic activity caused by the disease itself.
Collapse
Affiliation(s)
| | - Silvia Longhi
- Department of Pediatrics, General Hospital Bolzano, Bolzano, Italy
| | - Vittoria Cauvin
- Department of Pediatrics, Santa Chiara Hospital Trento, Trento, Italy
| | - Angelo Fassio
- Rheumatology Unit, University of Verona, Verona, Italy
| | - Giuseppe Gallo
- Department of Pediatrics, Santa Chiara Hospital Trento, Trento, Italy
| | - Fiorenzo Lupi
- Department of Pediatrics, General Hospital Bolzano, Bolzano, Italy
| | | | - Antonio Fanolla
- Department of Biostatistics, Regional Hospital Bolzano, Bolzano, Italy
| | - Davide Gatti
- Rheumatology Unit, University of Verona, Verona, Italy
| | - Giorgio Radetti
- Department of Pediatrics, General Hospital Bolzano, Bolzano, Italy.
- Marienklinik, Via Claudia De Medici, 2, 39100, Bolzano, Italy.
| |
Collapse
|
|
29
|
Napoli N, Strollo R, Defeudis G, Leto G, Moretti C, Zampetti S, D'Onofrio L, Campagna G, Palermo A, Greto V, Manfrini S, Hawa MI, Leslie RD, Pozzilli P, Buzzetti R. Serum Sclerostin and Bone Turnover in Latent Autoimmune Diabetes in Adults. J Clin Endocrinol Metab 2018; 103:1921-1928. [PMID: 29506222 DOI: 10.1210/jc.2017-02274] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 02/26/2018] [Indexed: 01/15/2023]
Abstract
PURPOSE Bone formation is impaired in both type 1 diabetes and type 2 diabetes (T2D), whereas sclerostin, an antagonist of bone formation, is increased in T2D only. No data are available on latent autoimmune diabetes in adults (LADA), an autoimmune type of diabetes that may clinically resemble T2D at diagnosis. We evaluated serum sclerostin and bone turnover markers in LADA compared with those in T2D and whether metabolic syndrome (MetS) affects sclerostin in T2D or LADA. METHODS This cross-sectional study included 98 patients with T2D and 89 with LADA from the Action LADA and Non Insulin Requiring Autoimmune Diabetes cohorts. Patients were further divided according to MetS status. Nondiabetic participants (n = 53) were used as controls. Serum sclerostin, bone formation (pro-collagen type 1 N-terminal propeptide [P1NP]), and bone resorption (C-terminal telopeptide of type I collagen [CTX]) were analyzed. RESULTS Patients with T2D had higher sclerostin than did those with LADA [P = 0.0008, adjusted for sex and body mass index (BMI)], even when analysis was restricted to patients with MetS (adjusted P = 0.03). Analysis of T2D and LADA groups separately showed that sclerostin was similar between those with and those without MetS. However, a positive trend between sclerostin and number of MetS features was seen with T2D (P for trend = 0.001) but not with LADA. Patients with T2D or LADA had lower CTX than did controls (P = 0.0003) and did not have significantly reduced P1NP. Sclerostin was unrelated to age or hemoglobin A1c but was correlated with BMI (ρ = 0.29; P = 0.0001), high-density lipoprotein (ρ = -0.23; P = 0.003), triglycerides (ρ = 0.19; P = 0.002), and time since diagnosis (ρ = 0.32; P < 0.0001). CONCLUSIONS Patients with LADA presented lower bone resorption than did controls, similar to patients with T2D. Sclerostin is increased in T2D but not in LADA, suggesting possible roles on bone metabolism in T2D only.
Collapse
Affiliation(s)
- Nicola Napoli
- Unit of Endocrinology and Diabetes, Department of Medicine, Universitá Campus Bio-Medico di Roma, Rome, Italy
- I.R.C.C.S. Istituto Ortopedico Galeazzi, Milan, Italy
| | - Rocky Strollo
- Unit of Endocrinology and Diabetes, Department of Medicine, Universitá Campus Bio-Medico di Roma, Rome, Italy
- Centre for Immunobiology, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom
| | - Giuseppe Defeudis
- Unit of Endocrinology and Diabetes, Department of Medicine, Universitá Campus Bio-Medico di Roma, Rome, Italy
| | - Gaetano Leto
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Chiara Moretti
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Simona Zampetti
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Luca D'Onofrio
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Giuseppe Campagna
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Andrea Palermo
- Unit of Endocrinology and Diabetes, Department of Medicine, Universitá Campus Bio-Medico di Roma, Rome, Italy
| | - Valentina Greto
- Unit of Endocrinology and Diabetes, Department of Medicine, Universitá Campus Bio-Medico di Roma, Rome, Italy
| | - Silvia Manfrini
- Unit of Endocrinology and Diabetes, Department of Medicine, Universitá Campus Bio-Medico di Roma, Rome, Italy
| | - Mohammed I Hawa
- Centre for Immunobiology, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom
| | - R David Leslie
- Centre for Immunobiology, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom
| | - Paolo Pozzilli
- Unit of Endocrinology and Diabetes, Department of Medicine, Universitá Campus Bio-Medico di Roma, Rome, Italy
- Centre for Immunobiology, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom
| | - Raffaella Buzzetti
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | | |
Collapse
|
|
30
|
Pinho RCM, Pimentel LB, Bandeira FAF, Dias RSAM, Cimões R. Levels of serum sclerostin, metabolic parameters, and periodontitis in -postmenopausal women with diabetes. SPECIAL CARE IN DENTISTRY 2017; 37:282-289. [PMID: 29194725 DOI: 10.1111/scd.12250] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Diabetes mellitus (DM) is a metabolic disease defined by hyperglycemia, which is associated with periodontal disease and exerts an effect on bone metabolism. The aim of this study was to determine serum levels of sclerostin in postmenopausal women with diabetes and determine a possible association with periodontal disease. Sixty-one postmenopausal women (32 with diabetes and 29 without diabetes) were evaluated. Blood was collected for biochemical analysis and the determination of serum sclerostin. The participants were also submitted to a clinical examination for the evaluation of periodontal status. A total of 75.4% of the volunteers had periodontal disease and levels serum sclerostin were altered in 48.7% of the patients with diabetes. In the diabetic population, mean levels of LDL (p = 0.035) and urea (p = 0.032) were higher in the patients without periodontal disease and the plaque index was higher in those with periodontal disease (p = 0.039). The prevalence of periodontal disease and the levels serum sclerostin were high in the postmenopausal women analyzed, but the data do not allow the determination of whether periodontal disease is related to high levels of this peptide.
Collapse
|
|
31
|
Abstract
Diabetes mellitus, both type 1 and type 2 (T2DM), is associated with decreased bone strength as well as increased fracture risk. Bone mineral density is decreased in type 1 diabetes but increased in T2DM, compared with controls. This suggests alterations in bone quality are a major player in the pathogenesis of fragility fractures in patients with diabetes. The link between diabetes and bone appears to be mediated by complex pathways, including the insulin-insulin growth factors system, accumulation of advanced glycation end-products in bone collagen, microangiopathy, and increased bone marrow fat content. Bone fragility in T2DM, which is not reflected by bone mineral density and bone mass reduction, depends on deterioration of bone quality. Also, at least in T2DM, the classical diagnosis of osteoporosis by dual-energy X-ray absorptiometry and the fracture risk estimation by FRAX (fracture risk assessment tool) are only partially useful in assessing fracture risk. Trabecular bone score and trabecular bone score-adjusted FRAX offer an enhanced estimation of fracture risk in these patients. Specific risk stratification criteria are needed in the future. The development of improved methods to assess the material properties of bone to better characterize fracture risk is also a priority. Adequate glycemic control is generally associated with decreased fracture risk, with the exception of specific antidiabetics (thiazolidinediones, canagliflozin) that have been shown to have a detrimental effect. Most currently used antiosteoporotic treatments seem equally effective in diabetic patients as compared with patients without diabetes, but clinical data regarding the reduction in fracture risk specifically in patients with diabetes mellitus are lacking.
Collapse
Affiliation(s)
- Catalina Poiana
- Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; C.I.Parhon National Institute of Endocrinology, Bucharest, Romania.
| | - Cristina Capatina
- Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; C.I.Parhon National Institute of Endocrinology, Bucharest, Romania
| |
Collapse
|
|
32
|
Raisingani M, Preneet B, Kohn B, Yakar S. Skeletal growth and bone mineral acquisition in type 1 diabetic children; abnormalities of the GH/IGF-1 axis. Growth Horm IGF Res 2017; 34:13-21. [PMID: 28482269 PMCID: PMC5516798 DOI: 10.1016/j.ghir.2017.04.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 04/23/2017] [Accepted: 04/27/2017] [Indexed: 12/29/2022]
Abstract
Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases diagnosed in childhood. Childhood and adolescent years are also the most important period for growth in height and acquisition of skeletal bone mineral density (BMD). The growth hormone (GH)/insulin like growth factor -1 (IGF-1) axis which regulates growth, is affected by T1DM, with studies showing increased GH and decreased IGF-1 levels in children with T1DM. There is conflicting data as to whether adolescents with TIDM are able to achieve their genetically-determined adult height. Furthermore, data support that adolescents with T1DM have decreased peak BMD, although the pathophysiology of which has not been completely defined. Various mechanisms have been proposed for the decrease in BMD including low osteocalcin levels, reflecting decreased bone formation; increased sclerostin, an inhibitor of bone anabolic pathways; and increased leptin, an adipocytokine which affects bone metabolism via central and peripheral mechanisms. Other factors implicated in the increased bone resorption in T1DM include upregulation of the osteoprotegerin/ receptor-activator of the nuclear factor-κB ligand pathway, elevated parathyroid hormone levels, and activation of other cytokines involved in chronic systemic inflammation. In this review, we summarize the clinical studies that address the alterations in the GH/IGF-I axis, linear growth velocity, and BMD in children and adolescents with T1DM; and we review the possible molecular mechanisms that may contribute to an attenuation of linear growth and to the reduction in the acquisition of peak bone mass in the child and adolescent with T1DM.
Collapse
Affiliation(s)
- Manish Raisingani
- Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, New York University School of Medicine, New York, NY 10016, United States
| | - Brar Preneet
- Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, New York University School of Medicine, New York, NY 10016, United States
| | - Brenda Kohn
- Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, New York University School of Medicine, New York, NY 10016, United States
| | - Shoshana Yakar
- David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY 10010-4086, United States.
| |
Collapse
|
|
33
|
Faienza MF, Ventura A, Delvecchio M, Fusillo A, Piacente L, Aceto G, Colaianni G, Colucci S, Cavallo L, Grano M, Brunetti G. High Sclerostin and Dickkopf-1 (DKK-1) Serum Levels in Children and Adolescents With Type 1 Diabetes Mellitus. J Clin Endocrinol Metab 2017; 102:1174-1181. [PMID: 28388723 DOI: 10.1210/jc.2016-2371] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 10/07/2016] [Indexed: 12/28/2022]
Abstract
CONTEXT Childhood type 1 diabetes mellitus (T1DM) is associated with decreased bone mass. Sclerostin and dickkopf-1 (DKK-1) are Wnt inhibitors that regulate bone formation. OBJECTIVE To evaluate sclerostin and DKK-1 levels in T1DM children and to analyze the influence of glycemic control on bone health. DESIGN AND SETTING Cross-sectional study conducted at a clinical research center. PARTICIPANTS One hundred and six T1DM subjects (12.2 ± 4 years), 66 on multiple daily injections (MDIs) and 40 on continuous subcutaneous infusion of insulin (CSII), and 80 controls. RESULTS The average bone transmission time (BTT) and amplitude-dependent speed of sound (AD-SoS) z scores were lower in patients with diabetes than in controls. Significantly increased DKK-1 (3593 ± 1172 vs 2652 ± 689 pg/mL; P < 0.006) and sclerostin (29.45 ± 12.32 vs 22.53 ± 8.29; P < 0.001) levels were found in patients with diabetes with respect to controls, particularly in patients on MDI compared with ones on CSII. Glycemic control was improved in CSII patients compared with MDI ones (P < 0.001) and was also associated with significantly higher BMI-SDS (P < 0.002) and BTT z scores (P < 0.02). With adjustment for age, multiple linear regression analysis of DKK-1 and sclerostin as dependent variables showed that levels of glycated hemoglobin, glucose, 25(OH) vitamin D, osteocalcin, and parathyroid hormone; years of diabetes; and BMI-SDS and AD-SoS z score were the most important predictors (P < 0.0001). CONCLUSIONS Our study highlighted (1) the high serum levels of DKK-1 and sclerostin in T1DM children and their relationship with altered glycemic control and (2) the effect of CSII on improvement of glycemic control and bone health in T1DM children.
Collapse
Affiliation(s)
| | - Annamaria Ventura
- Departments of Biomedical Science and Human Oncology, Pediatric Unit, and
| | | | - Anna Fusillo
- Departments of Biomedical Science and Human Oncology, Pediatric Unit, and
| | - Laura Piacente
- Departments of Biomedical Science and Human Oncology, Pediatric Unit, and
| | - Gabriella Aceto
- Departments of Biomedical Science and Human Oncology, Pediatric Unit, and
| | - Graziana Colaianni
- Basic and Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari A. Moro, 70124 Bari, Italy
| | - Silvia Colucci
- Basic and Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari A. Moro, 70124 Bari, Italy
| | - Luciano Cavallo
- Departments of Biomedical Science and Human Oncology, Pediatric Unit, and
| | - Maria Grano
- Department of Emergency and Organ Transplantation, University of Bari A. Moro, 70121 Bari, Italy
| | - Giacomina Brunetti
- Basic and Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari A. Moro, 70124 Bari, Italy
| |
Collapse
|
|
34
|
Hygum K, Starup-Linde J, Harsløf T, Vestergaard P, Langdahl BL. MECHANISMS IN ENDOCRINOLOGY: Diabetes mellitus, a state of low bone turnover - a systematic review and meta-analysis. Eur J Endocrinol 2017; 176:R137-R157. [PMID: 28049653 DOI: 10.1530/eje-16-0652] [Citation(s) in RCA: 214] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 10/31/2016] [Accepted: 11/15/2016] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To investigate the differences in bone turnover between diabetic patients and controls. DESIGN A systematic review and meta-analysis. METHODS A literature search was conducted using the databases Medline at PubMed and EMBASE. The free text search terms 'diabetes mellitus' and 'bone turnover', 'sclerostin', 'RANKL', 'osteoprotegerin', 'tartrate-resistant acid' and 'TRAP' were used. Studies were eligible if they investigated bone turnover markers in patients with diabetes compared with controls. Data were extracted by two reviewers. RESULTS A total of 2881 papers were identified of which 66 studies were included. Serum levels of the bone resorption marker C-terminal cross-linked telopeptide (-0.10 ng/mL (-0.12, -0.08)) and the bone formation markers osteocalcin (-2.51 ng/mL (-3.01, -2.01)) and procollagen type 1 amino terminal propeptide (-10.80 ng/mL (-12.83, -8.77)) were all lower in patients with diabetes compared with controls. Furthermore, s-tartrate-resistant acid phosphatase was decreased in patients with type 2 diabetes (-0.31 U/L (-0.56, -0.05)) compared with controls. S-sclerostin was significantly higher in patients with type 2 diabetes (14.92 pmol/L (3.12, 26.72)) and patients with type 1 diabetes (3.24 pmol/L (1.52, 4.96)) compared with controls. Also, s-osteoprotegerin was increased among patients with diabetes compared with controls (2.67 pmol/L (0.21, 5.14)). CONCLUSIONS Markers of both bone formation and bone resorption are decreased in patients with diabetes. This suggests that diabetes mellitus is a state of low bone turnover, which in turn may lead to more fragile bone. Altered levels of sclerostin and osteoprotegerin may be responsible for this.
Collapse
Affiliation(s)
- Katrine Hygum
- Department of Endocrinology and Internal MedicineAarhus University Hospital, Aarhus C, Denmark
| | - Jakob Starup-Linde
- Department of Endocrinology and Internal MedicineAarhus University Hospital, Aarhus C, Denmark
- Department of Infectious DiseasesAarhus University Hospital, Aarhus N, Denmark
| | - Torben Harsløf
- Department of Endocrinology and Internal MedicineAarhus University Hospital, Aarhus C, Denmark
| | - Peter Vestergaard
- Department of Clinical Medicine and EndocrinologyAalborg University Hospital, Aalborg, Denmark
| | - Bente L Langdahl
- Department of Endocrinology and Internal MedicineAarhus University Hospital, Aarhus C, Denmark
| |
Collapse
|
|
35
|
Abstract
The Wnt/β-catenin signaling pathway plays an essential role in osteoblast biology. Sclerostin is a soluble antagonist of Wnt/β-catenin signaling secreted primarily by osteocytes. Current evidence indicates that sclerostin likely functions as a local/paracrine regulator of bone metabolism rather than as an endocrine hormone. Nonetheless, circulating sclerostin levels in humans often reflect changes in the bone microenvironment, although there may be exceptions to this observation. Using existing assays, circulating sclerostin levels have been shown to be altered in response to both hormonal stimuli and across a variety of normal physiological and pathophysiological conditions. In both rodents and humans, parathyroid hormone provided either intermittently or continuously suppresses sclerostin levels. Likewise, most evidence from both human and animal studies supports a suppressive effect of estrogen on sclerostin levels. Efforts to examine non-hormonal/systemic regulation of sclerostin have in general shown less consistent findings or have provided associations rather than direct interventional information, with the exception of mechanosensory studies which have consistently demonstrated increased sclerostin levels with skeletal unloading, and conversely decreases in sclerostin with enhanced skeletal loading. Herein, we will review the existent literature on both hormonal and non-hormonal/systemic factors which have been studied for their impact on sclerostin regulation.
Collapse
Affiliation(s)
- Matthew T Drake
- Department of Endocrinology, Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA.
| | - Sundeep Khosla
- Department of Endocrinology, Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA
| |
Collapse
|
|
36
|
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.
Collapse
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.
| |
Collapse
|
|
37
|
Palermo A, D'Onofrio L, Buzzetti R, Manfrini S, Napoli N. Pathophysiology of Bone Fragility in Patients with Diabetes. Calcif Tissue Int 2017; 100:122-132. [PMID: 28180919 DOI: 10.1007/s00223-016-0226-3] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 12/20/2016] [Indexed: 02/07/2023]
Abstract
It has been well established that bone fragility is one of the chronic complications of diabetes mellitus, and both type 1 and type 2 diabetes are risk factors for fragility fractures. Diabetes may negatively affect bone health by unbalancing several pathways: bone formation, bone resorption, collagen formation, inflammatory cytokine, muscular and incretin system, bone marrow adiposity and calcium metabolism. The purpose of this narrative review is to explore the current understanding of pathophysiological pathways underlying bone fragility in diabetics. In particular, the review will focus on the peculiar cellular and molecular system impairment that may lead to increased risk of fracture in type 1 and type 2 diabetes.
Collapse
Affiliation(s)
- Andrea Palermo
- Diabetes and Bone network, Department Endocrinology and Diabetes, University Campus Bio-Medico of Rome, Via Alvaro del Portillo, 21 - 00128, Rome, Italy
| | - Luca D'Onofrio
- Department of Experimental Medicine, Polo Pontino, Sapienza University of Rome, Rome, Italy
| | - Raffaella Buzzetti
- Department of Experimental Medicine, Polo Pontino, Sapienza University of Rome, Rome, Italy
| | - Silvia Manfrini
- Diabetes and Bone network, Department Endocrinology and Diabetes, University Campus Bio-Medico of Rome, Via Alvaro del Portillo, 21 - 00128, Rome, Italy
| | - Nicola Napoli
- Diabetes and Bone network, Department Endocrinology and Diabetes, University Campus Bio-Medico of Rome, Via Alvaro del Portillo, 21 - 00128, Rome, Italy.
- Division of Bone and Mineral Diseases, Washington University in St Louis, St Louis, USA.
| |
Collapse
|
|
38
|
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.
Collapse
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
| |
Collapse
|
|
39
|
Abstract
The skeleton is adversely affected by type 1 diabetes (T1D). Patients with T1D of both sexes have an increased risk of fracture that begins in childhood and extends across the entire lifespan. T1D is characterized by mild to modest deficits in bone density, structure, and microarchitecture. Current evidence suggests that the observed bone deficits in T1D are the result of impaired bone formation rather than increased bone resorption. There is emerging data that bone quality is impaired in T1D, which may explain the findings that fracture risk is elevated out of proportion to the degree of bone mineral deficit. In this review, we summarize the current knowledge regarding the epidemiology of skeletal health in T1D. Given the high individual and societal burden of osteoporotic fracture, there is an urgent need to better understand the etiology of T1D-related bone disease so that clinical strategies to prevent fracture can be developed.
Collapse
Affiliation(s)
- David R Weber
- Division of Pediatric Endocrinology, University of Rochester, 601 Elmwood Ave, Box 690, Rochester, NY, 14642, USA.
| | - George Schwartz
- Division of Pediatric Nephrology, University of Rochester, 601 Elmwood Ave, Box 690, Rochester, NY, 14642, USA
| |
Collapse
|
|
40
|
Tsentidis C, Gourgiotis D, Kossiva L, Marmarinos A, Doulgeraki A, Karavanaki K. Sclerostin distribution in children and adolescents with type 1 diabetes mellitus and correlation with bone metabolism and bone mineral density. Pediatr Diabetes 2016; 17:289-99. [PMID: 26094958 DOI: 10.1111/pedi.12288] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Revised: 03/28/2015] [Accepted: 05/08/2015] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Sclerostin is an inhibitor of the Wnt/beta-catenin bone metabolic pathway. Increased sclerostin levels and reduced bone mineral density (BMD) have been documented in adult patients with diabetes mellitus (DM), predominantly in those with type 2 diabetes mellitus (T2DM). No relative data exist on childhood type 1 diabetes mellitus (T1DM). Our objective was to study plasma sclerostin in T1DM children and adolescents and controls and its correlations with metabolic bone markers and BMD. SUBJECTS AND METHODS This was a cross-sectional study that was conducted at an outpatient clinical center. Forty T1DM children and adolescents were evaluated (mean ± SD age: 13.04 ± 3.53 yr, T1DM duration: 5.15 ± 3.33 yr), along with 40 healthy matched controls (age 12.99 ± 3.3 yr). Sclerostin, soluble receptor activator of nuclear factor-kappaB ligand (s-RANKL), osteoprotegerin, osteocalcin, C-telopeptide crosslinks, electrolytes, parathyroid hormone (PTH), and total 25(OH)D were measured. Lumbar and subcranial total body BMD were evaluated with dual energy X-ray absorptiometry (DXA). RESULTS Sclerostin levels demonstrated a Gaussian distribution, with no significant difference between patients and controls (51.56 ± 12.05 vs. 50.98 ± 13.55 pmol/L, p = 0.84). Significantly lower values were found in girls and prepubertal children. Sclerostin values were significantly and gradually increased in children through pubertal Tanner stages 1-3, were reduced at stage 4 and increased again at pubertal stage 5. Sclerostin levels were positively correlated with logCTX (logarithm of C-terminal telopeptide crosslinks of type I collagen), logOsteocalcin (logarithm of Osteocalcin), magnesium, total body, and L1-L4 BMD z-score. CONCLUSIONS T1DM patients had similar levels of sclerostin with controls. Sclerostin correlated with bone resorption and formation markers and also with bone mass indices, gender, and pubertal stage. The decrease in sclerostin values observed in pubertal stage 4 adolescents coincides with the concurrent growth spurt, and is consistent with sclerostin physiology as an inhibiting signal.
Collapse
Affiliation(s)
- Charalampos Tsentidis
- Diabetic Clinic, 2nd Department of Pediatrics, Athens University Medical School, 'P&A Kyriakou' Children's Hospital, Athens, Greece
| | - Dimitrios Gourgiotis
- Laboratory of Clinical Biochemistry - Molecular Diagnostics, 2nd Department of Pediatrics, Athens University Medical School, 'P & A Kyriakou' Children's Hospital, Athens, Greece
| | - Lydia Kossiva
- Diabetic Clinic, 2nd Department of Pediatrics, Athens University Medical School, 'P&A Kyriakou' Children's Hospital, Athens, Greece
| | - Antonios Marmarinos
- Laboratory of Clinical Biochemistry - Molecular Diagnostics, 2nd Department of Pediatrics, Athens University Medical School, 'P & A Kyriakou' Children's Hospital, Athens, Greece
| | - Artemis Doulgeraki
- Department of Bone and Mineral Metabolism, Institute of Child Health, 'Aghia Sophia' Children's Hospital, Athens, Greece
| | - Kyriaki Karavanaki
- Diabetic Clinic, 2nd Department of Pediatrics, Athens University Medical School, 'P&A Kyriakou' Children's Hospital, Athens, Greece
| |
Collapse
|
|
41
|
Daniele G, Winnier D, Mari A, Bruder J, Fourcaudot M, Pengou Z, Tripathy D, Jenkinson C, Folli F. Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism. Diabetes Care 2015; 38:1509-17. [PMID: 26084344 DOI: 10.2337/dc14-2989] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 04/28/2015] [Indexed: 02/03/2023]
Abstract
OBJECTIVE A gene mutation of the Wnt/β-catenin signaling cascade is present in rare patients with the insulin resistance syndrome. Sclerostin is a circulating peptide inhibiting Wnt/β-catenin signaling. Our aims were to evaluate serum sclerostin in subjects with prediabetes and to analyze its relationship with insulin resistance and β-cell function. RESEARCH DESIGN AND METHODS We performed a cross-sectional study including 43 healthy normal glucose-tolerant (NGT) individuals and 79 individuals with impaired glucose regulation (IGR), which included subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG-IGT, undergoing oral glucose tolerance test (OGTT) and dual-energy X-ray absorptiometry. A subgroup of 18 with NGT and 30 with IGR also underwent a euglycemic-hyperinsulinemic clamp with tracer. RESULTS Sclerostin levels were higher in IGR compared with NGT (50.8 ± 2.4 vs. 38.7 ± 2.3 pmol/L; P = 0.01), positively correlated with HOMA-insulin resistance (IR) (r = 0.62; P < 0.001), and negatively correlated with insulin-mediated total body glucose disposal (r = -0.40; P < 0.001). Fasting endogenous glucose production (EGP) and hepatic and adipose tissue insulin resistance indexes were positively correlated with sclerostin levels (r = 0.48, r = 0.62, and r = 0.61, respectively; P < 0.001). Fasting and OGTT insulin clearance were inversely correlated with sclerostin serum levels (r = -0.52 and r = -0.44, respectively; both P < 0.001). Sclerostin levels were not correlated with β-cell function parameters. In multiple linear regression analysis, the addition of sclerostin levels to the traditional risk factors for insulin resistance improved the r(2) associated with HOMA-IR (r(2) change: 0.055; F change: 28.893; P = 0.001) and insulin-mediated total body glucose disposal (r(2) change: 0.059; F change: 4.938; P = 0.033). CONCLUSIONS Sclerostin levels are increased in individuals with prediabetes and correlated with insulin resistance in skeletal muscle, liver, and adipose tissue. The correlation between sclerostin and insulin clearance at fasting state and during OGTT is novel; thus, studies are needed to explore the potential causal relationship.
Collapse
Affiliation(s)
- Giuseppe Daniele
- Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Deidre Winnier
- Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Jan Bruder
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Marcel Fourcaudot
- Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Zuo Pengou
- Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Devjit Tripathy
- Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Christopher Jenkinson
- Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Franco Folli
- Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX Departamento de Clinica Medica, Faculdade de Ciencias Medicas, Obesity and Comorbidities Research Center, Universidade Estadual de Campinas, Campinas, Brazil
| |
Collapse
|
|
42
|
Kang J, Boonanantanasarn K, Baek K, Woo KM, Ryoo HM, Baek JH, Kim GS. Hyperglycemia increases the expression levels of sclerostin in a reactive oxygen species- and tumor necrosis factor-alpha-dependent manner. J Periodontal Implant Sci 2015; 45:101-10. [PMID: 26131370 PMCID: PMC4485060 DOI: 10.5051/jpis.2015.45.3.101] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 05/19/2015] [Indexed: 12/17/2022] Open
Affiliation(s)
- Jiho Kang
- Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Kanitsak Boonanantanasarn
- Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea. ; Department of Anatomy, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
| | - Kyunghwa Baek
- Department of Pharmacology, College of Dentistry, Gangneung-Wonju National University, Gangneung, Korea
| | - Kyung Mi Woo
- Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Hyun-Mo Ryoo
- Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Jeong-Hwa Baek
- Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Gwan-Shik Kim
- Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| |
Collapse
|
|
43
|
Type 1 diabetes and osteoporosis: from molecular pathways to bone phenotype. J Osteoporos 2015; 2015:174186. [PMID: 25874154 PMCID: PMC4385591 DOI: 10.1155/2015/174186] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 03/09/2015] [Indexed: 01/06/2023] Open
Abstract
The link between type 1 diabetes mellitus (DM1) and osteoporosis, identified decades ago, has gained attention in recent years. While a number of cellular mechanisms have been postulated to mediate this association, it is now established that defects in osteoblast differentiation and activity are the main culprits underlying bone fragility in DM1. Other contributing factors include an accumulation of advanced glycation end products (AGEs) and the development of diabetes complications (such as neuropathy and hypoglycemia), which cause further decline in bone mineral density (BMD), worsening geometric properties within bone, and increased fall risk. As a result, patients with DM1 have a 6.9-fold increased incidence of hip fracture compared to controls. Despite this increased fracture risk, bone fragility remains an underappreciated complication of DM1 and is not addressed in most diabetes guidelines. There is also a lack of data regarding the efficacy of therapeutic strategies to treat osteoporosis in this patient population. Together, our current understanding of bone fragility in DM1 calls for an update of diabetes guidelines, better screening tools, and further research into the use of therapeutic strategies in this patient population.
Collapse
|
|
44
|
Eaton GJ, Zhang QS, Diallo C, Matsuzawa A, Ichijo H, Steinbeck MJ, Freeman TA. Inhibition of apoptosis signal-regulating kinase 1 enhances endochondral bone formation by increasing chondrocyte survival. Cell Death Dis 2014; 5:e1522. [PMID: 25393478 PMCID: PMC4260738 DOI: 10.1038/cddis.2014.480] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 10/07/2014] [Indexed: 11/20/2022]
Abstract
Endochondral ossification is the result of chondrocyte differentiation, hypertrophy,
death and replacement by bone. The careful timing and progression of this process is
important for normal skeletal bone growth and development, as well as fracture
repair. Apoptosis Signal-Regulating Kinase 1 (ASK1) is a mitogen-activated protein
kinase (MAPK), which is activated by reactive oxygen species and other cellular
stress events. Activation of ASK1 initiates a signaling cascade known to regulate
diverse cellular events including cytokine and growth factor signaling, cell cycle
regulation, cellular differentiation, hypertrophy, survival and apoptosis. ASK1 is
highly expressed in hypertrophic chondrocytes, but the role of ASK1 in skeletal
tissues has not been investigated. Herein, we report that ASK1 knockout (KO) mice
display alterations in normal growth plate morphology, which include a shorter
proliferative zone and a lengthened hypertrophic zone. These changes in growth plate
dynamics result in accelerated long bone mineralization and an increased formation of
trabecular bone, which can be attributed to an increased resistance of terminally
differentiated chondrocytes to undergo cell death. Interestingly, under normal cell
culture conditions, mouse embryonic fibroblasts (MEFs) derived from ASK1 KO mice show
no differences in either MAPK signaling or osteogenic or chondrogenic differentiation
when compared with wild-type (WT) MEFs. However, when cultured with stress
activators, H2O2 or staurosporine, the KO cells show enhanced
survival, an associated decrease in the activation of proteins involved in death
signaling pathways and a reduction in markers of terminal differentiation.
Furthermore, in both WT mice treated with the ASK1 inhibitor, NQDI-1, and ASK1 KO
mice endochondral bone formation was increased in an ectopic ossification model.
These findings highlight a previously unrealized role for ASK1 in regulating
endochondral bone formation. Inhibition of ASK1 has clinical potential to treat
fractures or to slow osteoarthritic progression by enhancing chondrocyte survival and
slowing hypertrophy.
Collapse
Affiliation(s)
- G J Eaton
- Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Q-S Zhang
- 1] Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA [2] Department of Spine Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, PR China
| | - C Diallo
- Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - A Matsuzawa
- Laboratory of Cell Signaling, University of Tokyo, Tokyo 113-0033, Japan
| | - H Ichijo
- Open Innovation Center for Drug Discovery, University of Tokyo, Tokyo 113-0033, Japan
| | - M J Steinbeck
- School of Biomedical Engineering, Science & Health Systems, Drexel University, Philadelphia, PA 19104, USA
| | - T A Freeman
- Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA
| |
Collapse
|
|
45
|
Catalano A, Pintaudi B, Morabito N, Di Vieste G, Giunta L, Bruno ML, Cucinotta D, Lasco A, Di Benedetto A. Gender differences in sclerostin and clinical characteristics in type 1 diabetes mellitus. Eur J Endocrinol 2014; 171:293-300. [PMID: 24891138 DOI: 10.1530/eje-14-0106] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Sclerostin is an osteocyte-derived inhibitor of the Wnt/β-catenin signaling pathway, which acts as a negative regulator of bone formation. Published data on sclerostin levels in type 1 diabetes mellitus (T1DM) are few. OBJECTIVE To evaluate gender differences in sclerostin serum levels and the association among sclerostin, bone mass, bone metabolism, and the main clinical characteristics of subjects with T1DM. DESIGN AND METHODS A total of 69 patients with T1DM (mean age, 33.7±8.1; 49% males) were enrolled in this cross-sectional study in a clinical research center. Bone mineral density was measured by phalangeal quantitative ultrasound (QUS); bone turnover markers (urinary pyridinoline, deoxypyridinoline (D-PYR), and urine hydroxyproline (OH-PRO) to evaluate bone resorption; serum bone alkaline phosphatase and BGP to evaluate bone formation) and sclerostin were assessed. RESULTS D-PYR and sclerostin were significantly higher in women when compared with men (P=0.04). A disease duration >15 years was associated with higher sclerostin levels (P=0.03). Bone turnover markers and QUS parameters were not correlated with sclerostin. A significant negative correlation was observed among QUS parameters, BMI, and OH-PRO. Sclerostin serum levels were correlated with homocysteine (r=-0.34, P=0.005) and vitamin B12 (r=-0.31, P=0.02). Generalized linear model showed that macroangiopathy was the only predictor of sclerostin serum levels (β=-11.8, 95% CI from -21.9 to -1.7; P=0.02). CONCLUSIONS Our data demonstrate that women with T1DM exhibit higher sclerostin levels than men and that circulating sclerostin is not associated with bone turnover markers and phalangeal QUS measurements. Macroangiopathy was associated with sclerostin levels.
Collapse
Affiliation(s)
- Antonino Catalano
- Department of Clinical and Experimental MedicineUniversity Hospital of Messina, A.O.U. Policlinico 'G.Martino', Via C. Valeria, 98125 Messina, ItalyDepartment of Clinical Pharmacology and EpidemiologyFondazione Mario Negri Sud, Santa Maria Imbaro (CH), Italy
| | - Basilio Pintaudi
- Department of Clinical and Experimental MedicineUniversity Hospital of Messina, A.O.U. Policlinico 'G.Martino', Via C. Valeria, 98125 Messina, ItalyDepartment of Clinical Pharmacology and EpidemiologyFondazione Mario Negri Sud, Santa Maria Imbaro (CH), Italy
| | - Nancy Morabito
- Department of Clinical and Experimental MedicineUniversity Hospital of Messina, A.O.U. Policlinico 'G.Martino', Via C. Valeria, 98125 Messina, ItalyDepartment of Clinical Pharmacology and EpidemiologyFondazione Mario Negri Sud, Santa Maria Imbaro (CH), Italy
| | - Giacoma Di Vieste
- Department of Clinical and Experimental MedicineUniversity Hospital of Messina, A.O.U. Policlinico 'G.Martino', Via C. Valeria, 98125 Messina, ItalyDepartment of Clinical Pharmacology and EpidemiologyFondazione Mario Negri Sud, Santa Maria Imbaro (CH), Italy
| | - Loretta Giunta
- Department of Clinical and Experimental MedicineUniversity Hospital of Messina, A.O.U. Policlinico 'G.Martino', Via C. Valeria, 98125 Messina, ItalyDepartment of Clinical Pharmacology and EpidemiologyFondazione Mario Negri Sud, Santa Maria Imbaro (CH), Italy
| | - Maria Lucia Bruno
- Department of Clinical and Experimental MedicineUniversity Hospital of Messina, A.O.U. Policlinico 'G.Martino', Via C. Valeria, 98125 Messina, ItalyDepartment of Clinical Pharmacology and EpidemiologyFondazione Mario Negri Sud, Santa Maria Imbaro (CH), Italy
| | - Domenico Cucinotta
- Department of Clinical and Experimental MedicineUniversity Hospital of Messina, A.O.U. Policlinico 'G.Martino', Via C. Valeria, 98125 Messina, ItalyDepartment of Clinical Pharmacology and EpidemiologyFondazione Mario Negri Sud, Santa Maria Imbaro (CH), Italy
| | - Antonino Lasco
- Department of Clinical and Experimental MedicineUniversity Hospital of Messina, A.O.U. Policlinico 'G.Martino', Via C. Valeria, 98125 Messina, ItalyDepartment of Clinical Pharmacology and EpidemiologyFondazione Mario Negri Sud, Santa Maria Imbaro (CH), Italy
| | - Antonino Di Benedetto
- Department of Clinical and Experimental MedicineUniversity Hospital of Messina, A.O.U. Policlinico 'G.Martino', Via C. Valeria, 98125 Messina, ItalyDepartment of Clinical Pharmacology and EpidemiologyFondazione Mario Negri Sud, Santa Maria Imbaro (CH), Italy
| |
Collapse
|