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Kamml J, Acevedo C, Kammer DS. Mineral and cross-linking in collagen fibrils: The mechanical behavior of bone tissue at the nano-scale. J Mech Behav Biomed Mater 2024; 159:106697. [PMID: 39182252 PMCID: PMC11539549 DOI: 10.1016/j.jmbbm.2024.106697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/17/2024] [Accepted: 08/18/2024] [Indexed: 08/27/2024]
Abstract
The mineralized collagen fibril is the main building block of hard tissues and it directly affects the macroscopic mechanics of biological tissues such as bone. The mechanical behavior of the fibril itself is determined by its structure: the content of collagen molecules, minerals, and cross-links, and the mechanical interactions and properties of these components. Advanced glycation end products (AGEs) form cross-links between tropocollagen molecules within the collagen fibril and are one important factor that is believed to have a major influence on the tissue. For instance, it has been shown that brittleness in bone correlates with increased AGEs densities. However, the underlying nano-scale mechanisms within the mineralized collagen fibril remain unknown. Here, we study the effect of mineral and AGEs cross-linking on fibril deformation and fracture behavior by performing destructive tensile tests using coarse-grained molecular dynamics simulations. Our results demonstrate that after exceeding a critical content of mineral, it induces stiffening of the collagen fibril at high strain levels. We show that mineral morphology and location affect collagen fibril mechanics: The mineral content at which this stiffening occurs depends on the mineral's location and morphology. Further, both, increasing AGEs density and mineral content lead to stiffening and increased peak stresses. At low mineral contents, the mechanical response of the fibril is dominated by the AGEs, while at high mineral contents, the mineral itself determines fibril mechanics.
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Affiliation(s)
- Julia Kamml
- Institute for Building Materials, ETH Zurich, Switzerland
| | - Claire Acevedo
- Department of Mechanical and Aerospace Engineering, University of California San Diego, San Diego, CA, USA
| | - David S Kammer
- Institute for Building Materials, ETH Zurich, Switzerland.
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Chen Y, Zhao W, Hu A, Lin S, Chen P, Yang B, Fan Z, Qi J, Zhang W, Gao H, Yu X, Chen H, Chen L, Wang H. Type 2 diabetic mellitus related osteoporosis: focusing on ferroptosis. J Transl Med 2024; 22:409. [PMID: 38693581 PMCID: PMC11064363 DOI: 10.1186/s12967-024-05191-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 04/12/2024] [Indexed: 05/03/2024] Open
Abstract
With the aging global population, type 2 diabetes mellitus (T2DM) and osteoporosis(OP) are becoming increasingly prevalent. Diabetic osteoporosis (DOP) is a metabolic bone disorder characterized by abnormal bone tissue structure and reduced bone strength in patients with diabetes. Studies have revealed a close association among diabetes, increased fracture risk, and disturbances in iron metabolism. This review explores the concept of ferroptosis, a non-apoptotic cell death process dependent on intracellular iron, focusing on its role in DOP. Iron-dependent lipid peroxidation, particularly impacting pancreatic β-cells, osteoblasts (OBs) and osteoclasts (OCs), contributes to DOP. The intricate interplay between iron dysregulation, which comprises deficiency and overload, and DOP has been discussed, emphasizing how excessive iron accumulation triggers ferroptosis in DOP. This concise overview highlights the need to understand the complex relationship between T2DM and OP, particularly ferroptosis. This review aimed to elucidate the pathogenesis of ferroptosis in DOP and provide a prospective for future research targeting interventions in the field of ferroptosis.
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Affiliation(s)
- Yili Chen
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Wen Zhao
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - An Hu
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Shi Lin
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Ping Chen
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Bing Yang
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Zhirong Fan
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Ji Qi
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Wenhui Zhang
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Huanhuan Gao
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Xiubing Yu
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Haiyun Chen
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Luyuan Chen
- Stomatology Center, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, 510086, China.
| | - Haizhou Wang
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
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Kamml J, Acevedo C, Kammer DS. Mineral and cross-linking in collagen fibrils: The mechanical behavior of bone tissue at the nano-scale. ARXIV 2024:arXiv:2403.11753v1. [PMID: 38562451 PMCID: PMC10984003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
The mineralized collagen fibril is the main building block of hard tissues and it directly affects the macroscopic mechanics of biological tissues such as bone. The mechanical behavior of the fibril itself is determined by its structure: the content of collagen molecules, minerals, and cross-links, and the mechanical interactions and properties of these components. Advanced-Glycation-Endproducts (AGEs) cross-linking between tropocollagen molecules within the collagen fibril is one important factor that is believed to have a major influence on the tissue. For instance, it has been shown that brittleness in bone correlates with increased AGEs densities. However, the underlying nano-scale mechanisms within the mineralized collagen fibril remain unknown. Here, we study the effect of mineral and AGEs cross-linking on fibril deformation and fracture behavior by performing destructive tensile tests using coarse-grained molecular dynamics simulations. Our results demonstrate that after exceeding a critical content of mineral, it induces stiffening of the collagen fibril at high strain levels. We show that mineral morphology and location affect collagen fibril mechanics: The mineral content at which this stiffening occurs depends on the mineral's location and morphology. Further, both, increasing AGEs density and mineral content lead to stiffening and increased peak stresses. At low mineral contents, the mechanical response of the fibril is dominated by the AGEs, while at high mineral contents, the mineral itself determines fibril mechanics.
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Affiliation(s)
- Julia Kamml
- Institute for Building Materials, ETH Zurich, Switzerland
| | - Claire Acevedo
- Department of Mechanical and Aerospace Engineering, University of California San Diego, San Diego, California, USA
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Wang B, Vashishth D. Advanced glycation and glycoxidation end products in bone. Bone 2023; 176:116880. [PMID: 37579812 PMCID: PMC10529863 DOI: 10.1016/j.bone.2023.116880] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 07/21/2023] [Accepted: 08/11/2023] [Indexed: 08/16/2023]
Abstract
Hyperglycemia and oxidative stress, enhanced in diabetes and aging, result in excessive accumulation of advanced glycation and glycoxidation end products (AGEs/AGOEs) in bone. AGEs/AGOES are considered to be "the missing link" in explaining increased skeletal fragility with diabetes, aging, and osteoporosis where increased fracture risk cannot be solely explained by bone mass and/or fall incidences. AGEs/AGOEs disrupt bone turnover and deteriorate bone quality through alterations of organic matrix (collagen and non-collagenous proteins), mineral, and water content. AGEs and AGOEs are also associated with bone fragility in other conditions such as Alzheimer's disease, circadian rhythm disruption, and cancer. This review explains how AGEs and AGOEs accumulate in bone and impact bone quality and bone fracture, and how AGES/AGOEs are being targeted in preclinical and clinical investigations for inhibition or removal, and for prediction and management of diabetic, osteoporotic and insufficiency fractures.
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Affiliation(s)
- Bowen Wang
- Shirley Ann Jackson Ph.D. Center of Biotechnology and Interdisciplinary Studies, Troy, NY 12180, USA; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
| | - Deepak Vashishth
- Shirley Ann Jackson Ph.D. Center of Biotechnology and Interdisciplinary Studies, Troy, NY 12180, USA; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA; Rensselaer - Icahn School of Medicine at Mount Sinai Center for Engineering and Precision Medicine, New York, NY 10019, USA.
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Geduk¹ A, Oztas B, Eryılmaz BH, Demirsoy ET, Menguc MU, Unal S, Mersin S, Polat MG, Aygun K, Yenihayat EM, Albayrak H, Erol HA, Balcı S, Mehtap¹ O, Tarkun¹ P, Hacihanefioglu¹ A. Effects of AGEs, sRAGE and HMGB1 on Clinical Outcomes in Multiple Myeloma. Indian J Hematol Blood Transfus 2023; 39:220-227. [PMID: 37006982 PMCID: PMC10064350 DOI: 10.1007/s12288-022-01574-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 08/31/2022] [Indexed: 11/07/2022] Open
Abstract
Purpose The receptor for advanced glycation end products (RAGE) upregulated during the onset and progression of cancer and bone-related pathologies. In this study, we aimed to investigate the role of serum advanced glycation end products (AGEs), soluble RAGE (sRAGE) and high mobility group box 1 (HMGB1), in multiple myeloma (MM). Methods AGEs, sRAGE and HMGB1 concentrations of 54 newly diagnosed MM patients and 30 healthy volunteers were measured by ELISA. The estimations were done only once at diagnosis. The medical records of the patients were evaluated. Results There was no significant difference between the AGEs and sRAGE levels between the patient and control groups (p = 0.273, p = 0.313). In ROC analysis, a HMGB1 cutoff value of > 9170 pg/ml accurately discriminated MM patients (AUC = 0.672, 95% CI 0.561-0.77, p = 0.0034). AGEs level was found to be significantly higher in early-stage disease and HMGB1 in advanced disease (p = 0.022, p = 0.026). High HMGB1 levels were detected in patients whose with better first-line treatment response (p = 0.019). At 36 months, 54% of patients with low AGE were alive, compared to 79% of patients with high AGE (p = 0.055). Patients with high HMGB1 levels tended to have a longer PFS (median 43 mo [95% CI; 20.68-65.31] ) compared to patients with low HMGB1 levels (median 25 mo [95% CI; 12.39-37.6], p = 0.054). Conclusion In this study, a significant elevation of serum HMGB1 level was found in MM patients. In addition, the positive effects of RAGE ligands on treatment response and prognosis were determined.
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Affiliation(s)
- Ayfer Geduk¹
- Department of Hematology, Medical Faculty, Kocaeli University, 11.km, 41380 Umuttepe, Kocaeli, Turkey
| | - Berrin Oztas
- Department of Biochemistry, Medical Faculty, Kocaeli University, Kocaeli, Turkey
| | - Baldan Huri Eryılmaz
- Department of İnternal Medicine, Medical Faculty, Kocaeli University, Kocaeli, Turkey
| | - Esra Terzi Demirsoy
- Department of Hematology, Derince Training and Research Hospital, Health Sciences University, Kocaeli, Turkey
| | - Meral U. Menguc
- Department of Hematology, Medical Faculty, Bolu Abant İzzet Baysal University, Bolu, Turkey
| | - Serkan Unal
- Department of Hematology, Kastamonu Training and Research Hospital, Kastamonu, Turkey
| | - Sinan Mersin
- Department of Hematology, Medical Faculty, Kocaeli University, 11.km, 41380 Umuttepe, Kocaeli, Turkey
| | - Merve Gokcen Polat
- Department of Hematology, Medical Faculty, Kocaeli University, 11.km, 41380 Umuttepe, Kocaeli, Turkey
| | - Kemal Aygun
- Department of Hematology, Medical Faculty, Kocaeli University, 11.km, 41380 Umuttepe, Kocaeli, Turkey
| | - Emel Merve Yenihayat
- Department of Hematology, Medical Faculty, Kocaeli University, 11.km, 41380 Umuttepe, Kocaeli, Turkey
| | - Hayrunnisa Albayrak
- Department of Hematology, Medical Faculty, Kocaeli University, 11.km, 41380 Umuttepe, Kocaeli, Turkey
| | - Hasim Atakan Erol
- Department of Hematology, Medical Faculty, Kocaeli University, 11.km, 41380 Umuttepe, Kocaeli, Turkey
| | - Sibel Balcı
- Department of Biostatistics and Medical Informatics, Medical Faculty, Kocaeli University, Kocaeli, Turkey
| | - Ozgur Mehtap¹
- Department of Hematology, Medical Faculty, Kocaeli University, 11.km, 41380 Umuttepe, Kocaeli, Turkey
| | - Pinar Tarkun¹
- Department of Hematology, Medical Faculty, Kocaeli University, 11.km, 41380 Umuttepe, Kocaeli, Turkey
| | - Abdullah Hacihanefioglu¹
- Department of Hematology, Medical Faculty, Kocaeli University, 11.km, 41380 Umuttepe, Kocaeli, Turkey
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Liu CJ, Yang X, Wang SH, Wu XT, Mao Y, Shi JW, Fan YB, Sun LW. Preventing Disused Bone Loss through Inhibition of Advanced Glycation End Products. Int J Mol Sci 2023; 24:ijms24054953. [PMID: 36902384 PMCID: PMC10003672 DOI: 10.3390/ijms24054953] [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: 02/01/2023] [Revised: 02/26/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Bone loss occurs in astronauts during long-term space flight, but the mechanisms are still unclear. We previously showed that advanced glycation end products (AGEs) were involved in microgravity-induced osteoporosis. Here, we investigated the improvement effects of blocking AGEs formation on microgravity-induced bone loss by using the AGEs formation inhibitor, irbesartan. To achieve this objective, we used a tail-suspended (TS) rat model to simulate microgravity and treated the TS rats with 50 mg/kg/day irbesartan, as well as the fluorochrome biomarkers injected into rats to label dynamic bone formation. To assess the accumulation of AGEs, pentosidine (PEN), non-enzymatic cross-links (NE-xLR), and fluorescent AGEs (fAGEs) were identified in the bone; 8-hydroxydeoxyguanosine (8-OHdG) was analyzed for the reactive oxygen species (ROS) level in the bone. Meanwhile, bone mechanical properties, bone microstructure, and dynamic bone histomorphometry were tested for bone quality assessment, and Osterix and TRAP were immunofluorescences stained for the activities of osteoblastic and osteoclastic cells. Results showed AGEs increased significantly and 8-OHdG expression in bone showed an upward trend in TS rat hindlimbs. The bone quality (bone microstructure and mechanical properties) and bone formation process (dynamic bone formation and osteoblastic cells activities) were inhibited after tail-suspension, and showed a correlation with AGEs, suggesting the elevated AGEs contributed to the disused bone loss. After being treated with irbesartan, the increased AGEs and 8-OHdG expression were significantly inhibited, suggesting irbesartan may reduce ROS to inhibit dicarbonyl compounds, thus suppressing AGEs production after tail-suspension. The inhibition of AGEs can partially alter the bone remodeling process and improve bone quality. Both AGEs accumulation and bone alterations almost occurred in trabecular bone but not in cortical bone, suggesting AGEs effects on bone remodeling under microgravity are dependent on the biological milieu.
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Affiliation(s)
| | - Xiao Yang
- Correspondence: (X.Y.); (L.-W.S.); Tel.: +86-13811922096 (X.Y.); Fax: +86-10-82339349 (L.-W.S.)
| | | | | | | | | | | | - Lian-Wen Sun
- Correspondence: (X.Y.); (L.-W.S.); Tel.: +86-13811922096 (X.Y.); Fax: +86-10-82339349 (L.-W.S.)
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7
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Britton M, Parle E, Vaughan TJ. An investigation on the effects of in vitro induced advanced glycation end-products on cortical bone fracture mechanics at fall-related loading rates. J Mech Behav Biomed Mater 2023; 138:105619. [PMID: 36525877 DOI: 10.1016/j.jmbbm.2022.105619] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/06/2022] [Accepted: 12/08/2022] [Indexed: 12/13/2022]
Abstract
It has been suggested that adverse changes in bone quality due to the accumulation of advanced glycation end-products (AGEs) may play a role in the increased skeletal fragility. These non-enzymatic glycation mediated crosslinks are caused due to the presence of sugars in the extracellular space and can be induced in-vitro. AGEs exist naturally in bone, but with diseases such as type-2 diabetes, they are found at higher levels. While previous studies have examined the relationships between AGE accumulation and some mechanical properties, there is a lack of understanding of how AGE accumulation affects the fracture mechanics behaviour of bone tissue at fall-related loading rates. The objective of this study was to investigate the relationship between AGE accumulation and the fracture mechanics of cortical bone tissue. An in vitro glycation model was used to simulate diabetic conditions in twenty anatomically adjacent pairs of bone from a single bovine femur, which reduced the possibility of inter-specimen variability. Mechanical characterisation was carried out using 3-point bend, fracture toughness and nanoindentation testing, while bone composition was analysed by quantifying the accumulation of fluorescent AGEs. Under three-point bend testing, it was found that the yield stress, ultimate flexural strength, and secant modulus of the glycated samples were significantly higher than the controls. Furthermore, fracture toughness testing showed that the critical fracture toughness was increased by 16% in glycated samples compared to controls. These results provide no evidence that AGEs alone play a role in bone fragility at fall-related loading rates, with AGE accumulation actually found to enhance several pre- and post-yield properties of the tissue.
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Affiliation(s)
- Marissa Britton
- Biomechanics Research Centre (BioMEC), Biomedical Engineering, School of Engineering, College of Science and Engineering, University of Galway, Galway, Ireland
| | - Eoin Parle
- Department of Mechanical & Industrial Engineering, Atlantic Technological University, Galway, Ireland
| | - Ted J Vaughan
- Biomechanics Research Centre (BioMEC), Biomedical Engineering, School of Engineering, College of Science and Engineering, University of Galway, Galway, Ireland.
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Buettmann EG, Goldscheitter GM, Hoppock GA, Friedman MA, Suva LJ, Donahue HJ. Similarities Between Disuse and Age-Induced Bone Loss. J Bone Miner Res 2022; 37:1417-1434. [PMID: 35773785 PMCID: PMC9378610 DOI: 10.1002/jbmr.4643] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 06/17/2022] [Accepted: 06/24/2022] [Indexed: 11/07/2022]
Abstract
Disuse and aging are known risk factors associated with low bone mass and quality deterioration, resulting in increased fracture risk. Indeed, current and emerging evidence implicate a large number of shared skeletal manifestations between disuse and aging scenarios. This review provides a detailed overview of current preclinical models of musculoskeletal disuse and the clinical scenarios they seek to recapitulate. We also explore and summarize the major similarities between bone loss after extreme disuse and advanced aging at multiple length scales, including at the organ/tissue, cellular, and molecular level. Specifically, shared structural and material alterations of bone loss are presented between disuse and aging, including preferential loss of bone at cancellous sites, cortical thinning, and loss of bone strength due to enhanced fragility. At the cellular level bone loss is accompanied, during disuse and aging, by increased bone resorption, decreased formation, and enhanced adipogenesis due to altered gap junction intercellular communication, WNT/β-catenin and RANKL/OPG signaling. Major differences between extreme short-term disuse and aging are discussed, including anatomical specificity, differences in bone turnover rates, periosteal modeling, and the influence of subject sex and genetic variability. The examination also identifies potential shared mechanisms underlying bone loss in aging and disuse that warrant further study such as collagen cross-linking, advanced glycation end products/receptor for advanced glycation end products (AGE-RAGE) signaling, reactive oxygen species (ROS) and nuclear factor κB (NF-κB) signaling, cellular senescence, and altered lacunar-canalicular connectivity (mechanosensation). Understanding the shared structural alterations, changes in bone cell function, and molecular mechanisms common to both extreme disuse and aging are paramount to discovering therapies to combat both age-related and disuse-induced osteoporosis. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Evan G Buettmann
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, USA
| | - Galen M Goldscheitter
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, USA
| | - Gabriel A Hoppock
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, USA
| | - Michael A Friedman
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, USA
| | - Larry J Suva
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Henry J Donahue
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, USA
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3D Printed Scaffold Based on Type I Collagen/PLGA_TGF-β1 Nanoparticles Mimicking the Growth Factor Footprint of Human Bone Tissue. Polymers (Basel) 2022; 14:polym14050857. [PMID: 35267680 PMCID: PMC8912467 DOI: 10.3390/polym14050857] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/11/2022] [Accepted: 02/18/2022] [Indexed: 02/05/2023] Open
Abstract
In bone regenerative strategies, the controlled release of growth factors is one of the main aspects for successful tissue regeneration. Recent trends in the drug delivery field increased the interest in the development of biodegradable systems able to protect and transport active agents. In the present study, we designed degradable poly(lactic-co-glycolic)acid (PLGA) nanocarriers suitable for the release of Transforming Growth Factor-beta 1 (TGF-β1), a key molecule in the management of bone cells behaviour. Spherical TGF-β1-containing PLGA (PLGA_TGF-β1) nanoparticles (ca.250 nm) exhibiting high encapsulation efficiency (ca.64%) were successfully synthesized. The TGF-β1 nanocarriers were subsequently combined with type I collagen for the fabrication of nanostructured 3D printed scaffolds able to mimic the TGF-β1 presence in the human bone extracellular matrix (ECM). The homogeneous hybrid formulation underwent a comprehensive rheological characterisation in view of 3D printing. The 3D printed collagen-based scaffolds (10 mm × 10 mm × 1 mm) successfully mimicked the TGF-β1 presence in human bone ECM as assessed by immunohistochemical TGF-β1 staining, covering ca.3.4% of the whole scaffold area. Moreover, the collagenous matrix was able to reduce the initial burst release observed in the first 24 h from about 38% for the PLGA_TGF-β1 alone to 14.5%, proving that the nanocarriers incorporation into collagen allows achieving sustained release kinetics.
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Gao L, Liu C, Hu P, Wang N, Bao X, Wang B, Wang K, Li Y, Xue P. The role of advanced glycation end products in fracture risk assessment in postmenopausal type 2 diabetic patients. Front Endocrinol (Lausanne) 2022; 13:1013397. [PMID: 36578954 PMCID: PMC9790927 DOI: 10.3389/fendo.2022.1013397] [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: 08/07/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE The objective of this study was to analyze the quantitative association between advanced glycation end products (AGEs) and adjusted FRAX by rheumatoid arthritis (FRAX-RA) in postmenopausal type 2 diabetic (T2D) patients. The optimal cutoff value of AGEs was also explored, which was aimed at demonstrating the potential value of AGEs on evaluating osteoporotic fracture risk in postmenopausal T2D patients. METHODS We conducted a cross-sectional study including 366 postmenopausal participants (180 T2D patients [DM group] and 186 non-T2D individuals [NDM group]). All the subjects in each group were divided into three subgroups according to BMD. Physical examination, dual-energy x-ray absorptiometry (DXA), and serum indicators (including serum AGEs, glycemic parameters, bone turnover markers and inflammation factors) were examined. The relationship between FRAX-RA, serum laboratory variables, and AGEs were explored. The optimal cutoff value of AGEs to predict the risk of osteoporotic fracture was also investigated. RESULTS Adjusting the FRAX values with rheumatoid arthritis (RA) of T2D patients reached a significantly increased MOF-RA and an increasing trend of HF-RA. AGEs level was higher in the DM group compared to the NDMs, and was positively correlated with MOF-RA (r=0.682, P<0.001) and HF-RA (r=0.677, P<0.001). The receiver operating characteristic curve analysis revealed that the area under the curve was 0.804 (P<0.001), and the optimal AGEs cut-off value was 4.156mmol/L. Subgroup analysis for T2D patients revealed an increase in TGF-β, IL-6 and SCTX in the osteoporosis group, while a decreased PINP in the osteoporosis group compared to the other two subgroups. AGEs were positively associated with FBG, HbA1c, HOMA-IR, S-CTX, IL-6 and TGF-β in T2D patients, and negatively associated with PINP. CONCLUSIONS RA-adjusted FRAX is a relevant clinical tool in evaluating fracture risk of postmenopausal T2D patients. Our study analyzed the relationship between AGEs and FRAX-RA, and explored the threshold value of AGEs for predicting fracture risk in postmenopausal T2D patients. AGEs were also associated with serum bone turnover markers and inflammation factors, indicating that the increasing level of AGEs in postmenopausal T2D patients accelerated the expression of inflammatory factors, which led to bone metabolism disorders and a higher risk of osteoporotic fractures.
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Affiliation(s)
- Liu Gao
- Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Orthopedic Biomechanics of Hebei Province, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chang Liu
- Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Orthopedic Biomechanics of Hebei Province, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Pan Hu
- Trauma Medicine Center, Peking University People’s Hospital, Beijing, China
- National Center for Trauma Medicine, Peking University People's Hospital, Beijing, China
| | - Na Wang
- Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Orthopedic Biomechanics of Hebei Province, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaoxue Bao
- Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Orthopedic Biomechanics of Hebei Province, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Bin Wang
- Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Orthopedic Biomechanics of Hebei Province, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ke Wang
- Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Orthopedic Biomechanics of Hebei Province, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yukun Li
- Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Orthopedic Biomechanics of Hebei Province, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- *Correspondence: Peng Xue, ; Yukun Li,
| | - Peng Xue
- Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Orthopedic Biomechanics of Hebei Province, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- *Correspondence: Peng Xue, ; Yukun Li,
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11
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Mandair GS, Akhter MP, Esmonde-White FWL, Lappe JM, Bare SP, Lloyd WR, Long JP, Lopez J, Kozloff KM, Recker RR, Morris MD. Altered collagen chemical compositional structure in osteopenic women with past fractures: A case-control Raman spectroscopic study. Bone 2021; 148:115962. [PMID: 33862262 PMCID: PMC8259347 DOI: 10.1016/j.bone.2021.115962] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 03/25/2021] [Accepted: 04/08/2021] [Indexed: 12/17/2022]
Abstract
Incidences of low-trauma fractures among osteopenic women may be related to changes in bone quality. In this blinded, prospective-controlled study, compositional and heterogeneity contributors of bone quality to fracture risk were examined. We hypothesize that Raman spectroscopy can differentiate between osteopenic women with one or more fractures (cases) from women without fractures (controls). This study involved the Raman spectroscopic analysis of cortical and cancellous bone composition using iliac crest biopsies obtained from 59-cases and 59-controls, matched for age (62.0 ± 7.5 and 61.7 ± 7.3 years, respectively, p = 0.38) and hip bone mineral density (BMD, 0.827 ± 0.083 and 0.823 ± 0.072 g/cm3, respectively, p = 0.57). Based on aggregate univariate case-control and odds ratio based logistic regression analyses, we discovered two Raman ratiometric parameters that were predictive of past fracture risk. Specifically, 1244/1268 and 1044/959 cm-1 ratios, were identified as the most differential aspects of bone quality in cortical cases with odds ratios of 0.617 (0.406-0.938 95% CI, p = 0.024) and 1.656 (1.083-2.534 95% CI, p = 0.020), respectively. Both 1244/1268 and 1044/959 cm-1 ratios exhibited moderate sensitivity (59.3-64.4%) but low specificity (49.2-52.5%). These results suggest that the organization of mineralized collagen fibrils were significantly altered in cortical cases compared to controls. In contrast, compositional and heterogeneity parameters related to mineral/matrix ratios, B-type carbonate substitutions, and mineral crystallinity, were not significantly different between cases and controls. In conclusion, a key outcome of this study is the significant odds ratios obtained for two Raman parameters (1244/1268 and 1044/959 cm-1 ratios), which from a diagnostic perspective, may assist in the screening of osteopenic women with suspected low-trauma fractures. One important implication of these findings includes considering the possibility that changes in the organization of collagen compositional structure plays a far greater role in postmenopausal women with osteopenic fractures.
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Affiliation(s)
- Gurjit S Mandair
- School of Dentistry, Departments of Biologic and Materials, University of Michigan, Ann Arbor, MI, USA.
| | | | | | - Joan M Lappe
- Osteoporosis Research Center, Creighton University, Omaha, NE, USA
| | - Susan P Bare
- Osteoporosis Research Center, Creighton University, Omaha, NE, USA
| | - William R Lloyd
- Department of Chemistry, University of Michigan, Ann Arbor, MI, USA
| | - Jason P Long
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Jessica Lopez
- School of Dentistry, Departments of Biologic and Materials, University of Michigan, Ann Arbor, MI, USA
| | - Kenneth M Kozloff
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Robert R Recker
- Osteoporosis Research Center, Creighton University, Omaha, NE, USA
| | - Michael D Morris
- Department of Chemistry, University of Michigan, Ann Arbor, MI, USA
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12
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Ximenez JPB, Zamarioli A, Kacena MA, Barbosa RM, Barbosa F. Association of Urinary and Blood Concentrations of Heavy Metals with Measures of Bone Mineral Density Loss: a Data Mining Approach with the Results from the National Health and Nutrition Examination Survey. Biol Trace Elem Res 2021; 199:92-101. [PMID: 32356206 DOI: 10.1007/s12011-020-02150-7] [Citation(s) in RCA: 8] [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: 03/05/2020] [Accepted: 04/07/2020] [Indexed: 12/12/2022]
Abstract
Osteoporosis and its consequence of fragility fracture represent a major public health problem. Human exposure to heavy metals has received considerable attention over the last decades. However, little is known about the influence of co-exposure to multiple heavy metals on bone density. The present study aimed to examine the association between exposure to metals and bone mineral density (BMD) loss. Blood and urine concentrations of 20 chemical elements were selected from 3 cycles (2005-2010) NHANES (National Health and Nutrition Examination Survey), in which we included white women over 50 years of age and previously selected for BMD testing (N = 1892). The bone loss group was defined as participants having T-score < - 1.0, and the normal group was defined as participants having T-score ≥ - 1.0. We developed classification models based on support vector machines capable of determining which factors could best predict BMD loss. The model which included the five-best features-selected from the random forest were age, body mass index, urinary concentration of arsenic (As), cadmium (Cd), and tungsten (W), which have achieved high scores for accuracy (92.18%), sensitivity (90.50%), and specificity (93.35%). These data demonstrate the importance of these factors and metals to the classification since they alone were capable of generating a classification model with a high prediction of accuracy without requiring the other variables. In summary, our findings provide insight into the important, yet overlooked impact that arsenic, cadmium, and tungsten have on overall bone health.
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Affiliation(s)
- João Paulo B Ximenez
- Laboratório de Toxicologia Analítica e de Sistemas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, 14040-903, Brazil.
| | - Ariane Zamarioli
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Melissa A Kacena
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | | | - Fernando Barbosa
- Laboratório de Toxicologia Analítica e de Sistemas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, 14040-903, Brazil
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13
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Alcorta-Sevillano N, Macías I, Infante A, Rodríguez CI. Deciphering the Relevance of Bone ECM Signaling. Cells 2020; 9:E2630. [PMID: 33297501 PMCID: PMC7762413 DOI: 10.3390/cells9122630] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/03/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022] Open
Abstract
Bone mineral density, a bone matrix parameter frequently used to predict fracture risk, is not the only one to affect bone fragility. Other factors, including the extracellular matrix (ECM) composition and microarchitecture, are of paramount relevance in this process. The bone ECM is a noncellular three-dimensional structure secreted by cells into the extracellular space, which comprises inorganic and organic compounds. The main inorganic components of the ECM are calcium-deficient apatite and trace elements, while the organic ECM consists of collagen type I and noncollagenous proteins. Bone ECM dynamically interacts with osteoblasts and osteoclasts to regulate the formation of new bone during regeneration. Thus, the composition and structure of inorganic and organic bone matrix may directly affect bone quality. Moreover, proteins that compose ECM, beyond their structural role have other crucial biological functions, thanks to their ability to bind multiple interacting partners like other ECM proteins, growth factors, signal receptors and adhesion molecules. Thus, ECM proteins provide a complex network of biochemical and physiological signals. Herein, we summarize different ECM factors that are essential to bone strength besides, discussing how these parameters are altered in pathological conditions related with bone fragility.
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Affiliation(s)
| | | | - Arantza Infante
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, Barakaldo, 48903 Bizkaia, Spain; (N.A.-S.); (I.M.)
| | - Clara I. Rodríguez
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, Barakaldo, 48903 Bizkaia, Spain; (N.A.-S.); (I.M.)
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14
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Suzuki A, Yabu A, Nakamura H. Advanced glycation end products in musculoskeletal system and disorders. Methods 2020; 203:179-186. [PMID: 32987130 DOI: 10.1016/j.ymeth.2020.09.012] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/18/2020] [Accepted: 09/23/2020] [Indexed: 02/06/2023] Open
Abstract
The human population is ageing globally, and the number of old people is increasing yearly. Diabetes is common in the elderly, and the number of diabetic patients is also increasing. Elderly and diabetic patients often have musculoskeletal disorder, which are associated with advanced glycation end products (AGEs). AGEs are heterogeneous molecules derived from non-enzymatic products of the reaction of glucose or other sugar derivatives with proteins or lipids, and many different types of AGEs have been identified. AGEs are a biomarker for ageing and for evaluating disease conditions. Fluorescence, spectroscopy, mass spectrometry, chromatography, and immunological methods are commonly used to measure AGEs, but there is no standardized evaluation method because of the heterogeneity of AGEs. The formation of AGEs is irreversible, and they accumulate in tissue, eventually causing damage. AGE accumulation has been confirmed in neuromusculoskeletal tissues, including bones, cartilage, muscles, tendons, ligaments, and nerves, where they adversely affect biomechanical properties by causing charge changes and forming cross-linkages. AGEs also bind to receptors, such as the receptor for AGEs (RAGE), and induce inflammation by intracellular signal transduction. These mechanisms cause many varied aging and diabetes-related pathological conditions, such as osteoporosis, osteoarthritis, sarcopenia, tendinopathy, and neuropathy. Understanding of AGEs related pathomechanism may lead to develop novel methods for the prevention and therapy of such disorders which affect patients' quality of life. Herein, we critically review the current methodology used for detecting AGEs, and present potential mechanisms by which AGEs cause or exacerbate musculoskeletal disorders.
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Affiliation(s)
- Akinobu Suzuki
- Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Japan.
| | - Akito Yabu
- Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Japan
| | - Hiroaki Nakamura
- Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Japan
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15
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Saeki C, Saito M, Oikawa T, Nakano M, Torisu Y, Saruta M, Tsubota A. Effects of denosumab treatment in chronic liver disease patients with osteoporosis. World J Gastroenterol 2020; 26:4960-4971. [PMID: 32952342 PMCID: PMC7476181 DOI: 10.3748/wjg.v26.i33.4960] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/03/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Effective treatment of osteoporosis is essential for improving morbidity and health-related quality of life in chronic liver disease (CLD) patients. Denosumab has been shown to increase bone mineral density (BMD) and decrease the risk of osteoporotic fracture in the general population. However, there are few reports evaluating the efficacy of denosumab in CLD patients.
AIM To investigated the effects and safety of denosumab in CLD patients with osteoporosis.
METHODS Sixty CLD patients with osteoporosis were subcutaneously administered denosumab once every 6 mo. The study period for evaluating efficacy and safety was 12 mo. Changes from baseline in BMD at the lumbar spine, femoral neck, and total hip were evaluated at 12 mo of denosumab treatment. Bone turnover and quality were assessed by measuring serum tartrate-resistant acid phosphatase-5b (bone resorption marker), serum total procollagen type I N-terminal propeptide (bone formation maker), and plasma pentosidine (bone quality marker).
RESULTS Among the 405 CLD patients, 138 (34.1%) patients were diagnosed with osteoporosis; among these, 78 patients met the exclusion criteria and thus 60 patients were finally included in the present study. The median percentage changes from baseline to 12 mo of denosumab treatment in BMD at the lumbar spine, femoral neck, and total hip were +4.44%, +3.71%, and +4.03%, respectively. Denosumab significantly improved BMD, regardless of sex, patient age, and presence of liver cirrhosis. Serum tartrate-resistant acid phosphatase-5b and procollagen type I N-terminal propeptide levels constantly and significantly declined after denosumab treatment (P < 0.001). Plasma pentosidine levels were also significantly lower at 12 mo of treatment (P = 0.010). No patients experienced fractures and moderate-to-severe adverse events, except for transient hypocalcemia.
CONCLUSION Denosumab treatment was safe and increased BMD, suppressed bone turnover, and improved bone quality marker levels in CLD patients with osteoporosis, irrespective of differences in baseline characteristics.
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Affiliation(s)
- Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Masanori Nakano
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Yuichi Torisu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Akihito Tsubota
- Core Research Facilities, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo 1058461, Japan
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16
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Toni R, Di Conza G, Barbaro F, Zini N, Consolini E, Dallatana D, Antoniel M, Quarantini E, Quarantini M, Maioli S, Bruni CA, Elviri L, Panseri S, Sprio S, Sandri M, Tampieri A. Microtopography of Immune Cells in Osteoporosis and Bone Lesions by Endocrine Disruptors. Front Immunol 2020; 11:1737. [PMID: 33013826 PMCID: PMC7493744 DOI: 10.3389/fimmu.2020.01737] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 06/29/2020] [Indexed: 12/11/2022] Open
Abstract
Osteoporosis stems from an unbalance between bone mineral resorption and deposition. Among the numerous cellular players responsible for this unbalance bone marrow (BM) monocytes/macrophages, mast cells, T and B lymphocytes, and dendritic cells play a key role in regulating osteoclasts, osteoblasts, and their progenitor cells through interactions occurring in the context of the different bone compartments (cancellous and cortical). Therefore, the microtopography of immune cells inside trabecular and compact bone is expected to play a relevant role in setting initial sites of osteoporotic lesion. Indeed, in physiological conditions, each immune cell type preferentially occupies either endosteal, subendosteal, central, and/or perisinusoidal regions of the BM. However, in the presence of an activation, immune cells recirculate throughout these different microanatomical areas giving rise to a specific distribution. As a result, the trabeculae of the cancellous bone and endosteal free edge of the diaphyseal case emerge as the primary anatomical targets of their osteoporotic action. Immune cells may also transit from the BM to the depth of the compact bone, thanks to the efferent venous capillaries coursing in the Haversian and Volkmann canals. Consistently, the innermost parts of the osteons and the periosteum are later involved by their immunomodulatory action, becoming another site of mineral reabsorption in the course of an osteoporotic insult. The novelty of our updating is to highlight the microtopography of bone immune cells in the cancellous and cortical compartments in relation to the most consistent data on their action in bone remodeling, to offer a mechanist perspective useful to dissect their role in the osteoporotic process, including bone damage derived from the immunomodulatory effects of endocrine disrupting chemicals.
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Affiliation(s)
- Roberto Toni
- Laboratory of Regenerative Morphology and Bioartificial Structures (Re.Mo.Bio.S.), Department of Medicine and Surgery - DIMEC, Unit of Biomedical, Biotechnological and Translational Sciences (S.BI.BI.T.), Museum and Historical Library of Biomedicine - BIOMED, University of Parma, Parma, Italy.,OSTEONET-CMG Unit (Osteoporosis, Nutrition, Endocrinology, and Innovative Therapies) at the Medical Center Galliera (CMG), San Venanzio, Italy.,Interdepartment Center for Law, Economics, and Medicine of Sport, University of Parma, Parma, Italy.,Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States
| | - Giusy Di Conza
- Laboratory of Regenerative Morphology and Bioartificial Structures (Re.Mo.Bio.S.), Department of Medicine and Surgery - DIMEC, Unit of Biomedical, Biotechnological and Translational Sciences (S.BI.BI.T.), Museum and Historical Library of Biomedicine - BIOMED, University of Parma, Parma, Italy
| | - Fulvio Barbaro
- Laboratory of Regenerative Morphology and Bioartificial Structures (Re.Mo.Bio.S.), Department of Medicine and Surgery - DIMEC, Unit of Biomedical, Biotechnological and Translational Sciences (S.BI.BI.T.), Museum and Historical Library of Biomedicine - BIOMED, University of Parma, Parma, Italy
| | - Nicoletta Zini
- CNR- National Research Council of Italy, Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza" - Unit of Bologna, Bologna, Italy.,IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Elia Consolini
- Laboratory of Regenerative Morphology and Bioartificial Structures (Re.Mo.Bio.S.), Department of Medicine and Surgery - DIMEC, Unit of Biomedical, Biotechnological and Translational Sciences (S.BI.BI.T.), Museum and Historical Library of Biomedicine - BIOMED, University of Parma, Parma, Italy
| | - Davide Dallatana
- Laboratory of Regenerative Morphology and Bioartificial Structures (Re.Mo.Bio.S.), Department of Medicine and Surgery - DIMEC, Unit of Biomedical, Biotechnological and Translational Sciences (S.BI.BI.T.), Museum and Historical Library of Biomedicine - BIOMED, University of Parma, Parma, Italy
| | - Manuela Antoniel
- Laboratory of Regenerative Morphology and Bioartificial Structures (Re.Mo.Bio.S.), Department of Medicine and Surgery - DIMEC, Unit of Biomedical, Biotechnological and Translational Sciences (S.BI.BI.T.), Museum and Historical Library of Biomedicine - BIOMED, University of Parma, Parma, Italy.,IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Enrico Quarantini
- OSTEONET-CMG Unit (Osteoporosis, Nutrition, Endocrinology, and Innovative Therapies) at the Medical Center Galliera (CMG), San Venanzio, Italy
| | - Marco Quarantini
- OSTEONET-CMG Unit (Osteoporosis, Nutrition, Endocrinology, and Innovative Therapies) at the Medical Center Galliera (CMG), San Venanzio, Italy
| | - Sara Maioli
- Laboratory of Regenerative Morphology and Bioartificial Structures (Re.Mo.Bio.S.), Department of Medicine and Surgery - DIMEC, Unit of Biomedical, Biotechnological and Translational Sciences (S.BI.BI.T.), Museum and Historical Library of Biomedicine - BIOMED, University of Parma, Parma, Italy
| | - Celeste Angela Bruni
- Laboratory of Regenerative Morphology and Bioartificial Structures (Re.Mo.Bio.S.), Department of Medicine and Surgery - DIMEC, Unit of Biomedical, Biotechnological and Translational Sciences (S.BI.BI.T.), Museum and Historical Library of Biomedicine - BIOMED, University of Parma, Parma, Italy
| | - Lisa Elviri
- Food and Drug Department, University of Parma, Parma, Italy
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17
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Zamarioli A, de Andrade Staut C, Volpon JB. Review of Secondary Causes of Osteoporotic Fractures Due to Diabetes and Spinal Cord Injury. Curr Osteoporos Rep 2020; 18:148-156. [PMID: 32147752 DOI: 10.1007/s11914-020-00571-w] [Citation(s) in RCA: 4] [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] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW The aim of this review is to gain a better understanding of osteoporotic fractures and the different mechanisms that are driven in the scenarios of bone disuse due to spinal cord injury and osteometabolic disorders due to diabetes. RECENT FINDINGS Despite major advances in understanding the pathogenesis, prevention, and treatment of osteoporosis, the high incidence of impaired fracture healing remains an important complication of bone loss, leading to marked impairment of the health of an individual and economic burden to the medical system. This review underlines several pathways leading to bone loss and increased risk for fractures. Specifically, we addressed the different mechanisms leading to bone loss after a spinal cord injury and diabetes. Finally, it also encompasses the changes responsible for impaired bone repair in these scenarios, which may be of great interest for future studies on therapeutic approaches to treat osteoporosis and osteoporotic fractures.
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Affiliation(s)
- Ariane Zamarioli
- Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
| | - Caio de Andrade Staut
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - José B Volpon
- Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
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18
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Parle E, Tio S, Behre A, Carey JJ, Murphy CG, O'Brien TF, Curtin WA, Kearns SR, McCabe JP, Coleman CM, Vaughan TJ, McNamara LM. Bone Mineral Is More Heterogeneously Distributed in the Femoral Heads of Osteoporotic and Diabetic Patients: A Pilot Study. JBMR Plus 2020; 4:e10253. [PMID: 32149268 PMCID: PMC7017882 DOI: 10.1002/jbm4.10253] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/23/2019] [Accepted: 11/03/2019] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis is associated with systemic bone loss, leading to a significant deterioration of bone microarchitecture and an increased fracture risk. Although recent studies have shown that the distribution of bone mineral becomes more heterogeneous because of estrogen deficiency in animal models of osteoporosis, it is not known whether osteoporosis alters mineral distribution in human bone. Type 2 diabetes mellitus (T2DM) can also increase bone fracture risk and is associated with impaired bone cell function, compromised collagen structure, and reduced mechanical properties. However, it is not known whether alterations in mineral distribution arise in diabetic (DB) patients’ bone. In this study, we quantify mineral content distribution and tissue microarchitecture (by μCT) and mechanical properties (by compression testing) of cancellous bone from femoral heads of osteoporotic (OP; n = 10), DB (n = 7), and osteoarthritic (OA; n = 7) patients. We report that though OP cancellous bone has significantly deteriorated compressive mechanical properties and significantly compromised microarchitecture compared with OA controls, there is also a significant increase in the mean mineral content. Moreover, the heterogeneity of the mineral content in OP bone is significantly higher than controls (+25%) and is explained by a significant increase in bone volume at high mineral levels. We propose that these mineral alterations act to exacerbate the already reduced bone quality caused by reduced cancellous bone volume during osteoporosis. We show for the first time that cancellous bone mineralization is significantly more heterogeneous (+26%) in patients presenting with T2DM compared with OA (non‐DB) controls, and that this heterogeneity is characterized by a significant increase in bone volume at low mineral levels. Despite these mineralization changes, bone microarchitecture and mechanical properties are not significantly different between OA groups with and without T2DM. Nonetheless, the observed alterations in mineral heterogeneity may play an important tissue‐level role in bone fragility associated with OP and DB bone. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Eoin Parle
- Department of Biomedical Engineering National University of Ireland Galway Galway Ireland
| | - Sherdya Tio
- Department of Biomedical Engineering National University of Ireland Galway Galway Ireland
| | - Annie Behre
- Department of Bioengineering Lehigh University Bethlehem PA USA
| | - John J Carey
- Department of Rheumatology Galway University Hospitals Galway Ireland
| | - Colin G Murphy
- Department of Orthopaedics Galway University Hospitals Galway Ireland
| | - Timothy F O'Brien
- Department of Endocrinology Galway University Hospitals Galway Ireland
| | - William A Curtin
- Department of Orthopaedics Galway University Hospitals Galway Ireland
| | - Stephen R Kearns
- Department of Orthopaedics Galway University Hospitals Galway Ireland
| | - John P McCabe
- Department of Orthopaedics Galway University Hospitals Galway Ireland
| | - Cynthia M Coleman
- Department of Biomedical Engineering National University of Ireland Galway Galway Ireland
| | - Ted J Vaughan
- Department of Biomedical Engineering National University of Ireland Galway Galway Ireland
| | - Laoise M McNamara
- Department of Biomedical Engineering National University of Ireland Galway Galway Ireland
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19
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Strieder-Barboza C, Baker NA, Flesher CG, Karmakar M, Neeley CK, Polsinelli D, Dimick JB, Finks JF, Ghaferi AA, Varban OA, Lumeng CN, O'Rourke RW. Advanced glycation end-products regulate extracellular matrix-adipocyte metabolic crosstalk in diabetes. Sci Rep 2019; 9:19748. [PMID: 31875018 PMCID: PMC6930305 DOI: 10.1038/s41598-019-56242-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 12/07/2019] [Indexed: 12/28/2022] Open
Abstract
The adipose tissue extracellular matrix (ECM) regulates adipocyte cellular metabolism and is altered in obesity and type 2 diabetes, but mechanisms underlying ECM-adipocyte metabolic crosstalk are poorly defined. Advanced glycation end-product (AGE) formation is increased in diabetes. AGE alter tissue function via direct effects on ECM and by binding scavenger receptors on multiple cell types and signaling through Rho GTPases. Our goal was to determine the role and underlying mechanisms of AGE in regulating human ECM-adipocyte metabolic crosstalk. Visceral adipocytes from diabetic and non-diabetic humans with obesity were studied in 2D and 3D-ECM culture systems. AGE is increased in adipose tissue from diabetic compared to non-diabetic subjects. Glycated collagen 1 and AGE-modified ECM regulate adipocyte glucose uptake and expression of AGE scavenger receptors and Rho signaling mediators, including the DIAPH1 gene, which encodes the human Diaphanous 1 protein (hDia1). Notably, inhibition of hDia1, but not scavenger receptors RAGE or CD36, attenuated AGE-ECM inhibition of adipocyte glucose uptake. These data demonstrate that AGE-modification of ECM contributes to adipocyte insulin resistance in human diabetes, and implicate hDia1 as a potential mediator of AGE-ECM-adipocyte metabolic crosstalk.
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Affiliation(s)
- Clarissa Strieder-Barboza
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Nicki A Baker
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Carmen G Flesher
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Monita Karmakar
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Christopher K Neeley
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Dominic Polsinelli
- Undergraduate Research Opportunity Program, University of Michigan, Ann Arbor, MI, USA
| | - Justin B Dimick
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Jonathan F Finks
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Amir A Ghaferi
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Oliver A Varban
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Carey N Lumeng
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
- Graduate Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Robert W O'Rourke
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
- Department of Surgery, Ann Arbor Veterans Affairs Healthcare System, Ann Arbor, MI, USA.
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Tanaka K, Yamagata K, Kubo S, Nakayamada S, Sakata K, Matsui T, Yamagishi SI, Okada Y, Tanaka Y. Glycolaldehyde-modified advanced glycation end-products inhibit differentiation of human monocytes into osteoclasts via upregulation of IL-10. Bone 2019; 128:115034. [PMID: 31421252 DOI: 10.1016/j.bone.2019.115034] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 07/17/2019] [Accepted: 08/06/2019] [Indexed: 12/22/2022]
Abstract
Diabetes patients are at high risk of bone fracture due to accumulation of advanced glycation end products (AGEs) and low bone turnover. Although AGEs inhibit osteoblast functions, little is known about their roles in regulation of human osteoclast differentiation. The aim of this study was to determine the roles of AGEs in regulation of human osteoclast differentiation. Human CD14+ monocytes collected from healthy individuals were stimulated in vitro with conventional cytokines to induce osteoclast differentiation. Simultaneously, glucose-modified AGEs-BSA (Glu-AGEs-BSA) and glycolaldehyde-modified AGEs-BSA (Glyco-AGEs-BSA) were added to analyze their role in regulation of osteoclast differentiation. Human CD14+ cells expressed endogenous receptor for AGE (RAGE). Stimulation with Glyco-AGEs-BSA, but not Glu-AGEs-BSA, reduced the number of tartrate-resistant acid phosphatase-positive cells in a dose-dependent manner and suppressed mRNA expression of nuclear factor of activated T-cells 1 and cathepsin K. Glyco-AGEs-BSA up-regulated pro-inflammatory cytokines and anti-inflammatory cytokine IL-10. The addition of IL-10-neutralizing antibodies abrogated the suppressive effect of Glyco-AGEs-BSA on osteoclast differentiation. Stimulation of Glyco-AGE-BSA resulted in nuclear factor (NF)-κB phosphorylation, and addition of an inhibitor of κB kinase suppressed IL-10 production. We conclude that Glyco-AGEs-BSA inhibited human osteoclast differentiation through induction of IL-10 expression via NF-κB. It can be assumed that AGE bioaccumulation in diabetic patients increases the risk of bone fracture, through inhibition of osteoclast differentiation, reduction of bone turnover, and disruption of bone remodeling.
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Affiliation(s)
- Kenichi Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan
| | - Kaoru Yamagata
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan
| | - Satoshi Kubo
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan
| | - Shingo Nakayamada
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan
| | - Kei Sakata
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan; Mitsubishi Tanabe Pharma Corporation, Yokohama 227-0033, Japan
| | - Takanori Matsui
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Sho-Ichi Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Yosuke Okada
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan.
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21
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Licini C, Vitale-Brovarone C, Mattioli-Belmonte M. Collagen and non-collagenous proteins molecular crosstalk in the pathophysiology of osteoporosis. Cytokine Growth Factor Rev 2019; 49:59-69. [PMID: 31543432 DOI: 10.1016/j.cytogfr.2019.09.001] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 09/12/2019] [Accepted: 09/12/2019] [Indexed: 01/07/2023]
Abstract
Collagenous and non-collagenous proteins (NCPs) in the extracellular matrix, as well as the coupling mechanisms between osteoclasts and osteoblasts, work together to ensure normal bone metabolism. Each protein plays one or more critical roles in bone metabolism, sometimes even contradictory, thus affecting the final mechanical, physical and chemical properties of bone tissue. Anomalies in the amount and structure of one or more of these proteins can cause abnormalities in bone formation and resorption, which consequently leads to malformations and defects, such as osteoporosis (OP). The connections between key proteins involved in matrix formation and resorption are far from being elucidated. In this review, we resume knowledge on the crosstalk between collagen type I and selected NCPs (Transforming Growth Factor-β, Insulin-like Growth Factor-1, Decorin, Osteonectin, Osteopontin, Bone Sialoprotein and Osteocalcin) of bone matrix, focusing on their possible involvement and role in OP. The different elements of this network can be pharmacologically targeted or used for the design/development of innovative regenerative strategies to modulate a feedback loop in bone remodelling.
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Affiliation(s)
- Caterina Licini
- Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129, Torino, Italy; Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Via Tronto 10/a, 60126, Ancona, Italy
| | - Chiara Vitale-Brovarone
- Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129, Torino, Italy.
| | - Monica Mattioli-Belmonte
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Via Tronto 10/a, 60126, Ancona, Italy
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22
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Glycation-induced modification of tissue-specific ECM proteins: A pathophysiological mechanism in degenerative diseases. Biochim Biophys Acta Gen Subj 2019; 1863:129411. [PMID: 31400438 DOI: 10.1016/j.bbagen.2019.08.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 07/29/2019] [Accepted: 08/05/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Glycation driven generation of advanced glycation end products (AGEs) and their patho-physiological role in human degenerative diseases has remained one of the thrust areas in the mainstream of disease biology. Glycation of extracellular matrix (ECM) proteins have deleterious effect on the mechanical and functional properties of tissues. Owing to the adverse pathophysiological concerns of glycation, there is a need to decipher the underlying mechanisms. SCOPE OF REVIEW AGE-modified ECM proteins affect the cell in the vicinity by altering protein structure-function, matrix-matrix or matrix-cell interaction and by activating signalling pathway through receptor for AGE. This review is intended for addressing the AGE-induced modification of tissue-specific ECM proteins and its implication in the pathogenesis of various organ-specific human ailments. MAJOR CONCLUSIONS The glycation affects the canonical cell behaviour due to alteration in the interaction of glycated ECM with receptors like integrins and discodin domain, and the signalling cues generated subsequently affect the downstream signalling pathways. Consequently, the variation of structural and functional properties of tissues due to matrix glycation helps in the initiation or progression of the disease condition. GENERAL SIGNIFICANCE This review offers comprehensive knowledge about the remodelling of glycation induced ECM and tissue-specific pathological concerns. As glycation of ECM affects the normal tissues and cell behaviour, the scientific discourse may also provide cues for developing candidate drugs that may help in attenuating the adverse effects of AGEs and perhaps open a research window of tailoring novel strategies for the management of glycation induced human degenerative diseases.
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23
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Asadipooya K, Uy EM. Advanced Glycation End Products (AGEs), Receptor for AGEs, Diabetes, and Bone: Review of the Literature. J Endocr Soc 2019; 3:1799-1818. [PMID: 31528827 PMCID: PMC6734192 DOI: 10.1210/js.2019-00160] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 07/03/2019] [Indexed: 12/24/2022] Open
Abstract
Diabetes compromises bone cell metabolism and function, resulting in increased risk of fragility fracture. Advanced glycation end products (AGEs) interact with the receptor for AGEs (RAGE) and can make a meaningful contribution to bone cell metabolism and/or alter function. Searches in PubMed using the key words "advanced glycation end-product," "RAGE," "sRAGE," "bone," and "diabetes" were made to explain some of the clinical outcomes of diabetes in bone metabolism through the AGE-RAGE signaling pathway. All published clinical studies were included in tables. The AGE-RAGE signaling pathway participates in diabetic complications, including diabetic osteopathy. Some clinical results in diabetic patients, such as reduced bone density, suppressed bone turnover markers, and bone quality impairment, could be potentially due to AGE-RAGE signaling consequences. However, the AGE-RAGE signaling pathway has some helpful roles in the bone, including an increase in osteogenic function. Soluble RAGE (sRAGE), as a ligand decoy, may increase in either conditions of RAGE production or destruction, and then it cannot always reflect the AGE-RAGE signaling. Recombinant sRAGE can block the AGE-RAGE signaling pathway but is associated with some limitations, such as accessibility to AGEs, an increase in other RAGE ligands, and a long half-life (24 hours), which is associated with losing the beneficial effect of AGE/RAGE. As a result, sRAGE is not a helpful marker to assess activity of the RAGE signaling pathway. The recombinant sRAGE cannot be translated into clinical practice due to its limitations.
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Affiliation(s)
- Kamyar Asadipooya
- Division of Endocrinology and Molecular Medicine, Department of Medicine, University of Kentucky, Lexington, Kentucky
| | - Edilfavia Mae Uy
- Division of Endocrinology and Molecular Medicine, Department of Medicine, University of Kentucky, Lexington, Kentucky
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24
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Davis HM, Valdez S, Gomez L, Malicky P, White FA, Subler MA, Windle JJ, Bidwell JP, Bruzzaniti A, Plotkin LI. High mobility group box 1 protein regulates osteoclastogenesis through direct actions on osteocytes and osteoclasts in vitro. J Cell Biochem 2019; 120:16741-16749. [PMID: 31106449 DOI: 10.1002/jcb.28932] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 04/24/2019] [Indexed: 12/30/2022]
Abstract
Old age and Cx43 deletion in osteocytes are associated with increased osteocyte apoptosis and osteoclastogenesis. We previously demonstrated that apoptotic osteocytes release elevated concentrations of the proinflammatory cytokine, high mobility group box 1 protein (HMGB1) and apoptotic osteocyte conditioned media (CM) promotes osteoclast differentiation. Further, prevention of osteocyte apoptosis blocks osteoclast differentiation and attenuates the extracellular release of HMGB1 and RANKL. Moreover, sequestration of HMGB1, in turn, reduces RANKL production/release by MLO-Y4 osteocytic cells silenced for Cx43 (Cx43def ), highlighting the possibility that HMGB1 promotes apoptotic osteocyte-induced osteoclastogenesis. However, the role of HMGB1 signaling in osteocytes has not been well studied. Further, the mechanisms underlying its release and the receptor(s) responsible for its actions is not clear. We now report that a neutralizing HMGB1 antibody reduces osteoclast formation in RANKL/M-CSF treated bone marrow cells. In bone marrow macrophages (BMMs), toll-like receptor 4 (TLR4) inhibition with LPS-RS, but not receptor for advanced glycation end products (RAGE) inhibition with Azeliragon attenuated osteoclast differentiation. Further, inhibition of RAGE but not of TLR4 in osteoclast precursors reduced osteoclast number, suggesting that HGMB1 produced by osteoclasts directly affects differentiation by activating TLR4 in BMMs and RAGE in preosteoclasts. Our findings also suggest that increased osteoclastogenesis induced by apoptotic osteocytes CM is not mediated through HMGB1/RAGE activation and that direct HMGB1 actions in osteocytes stimulate pro-osteoclastogenic signal release from Cx43def osteocytes. Based on these findings, we propose that HMGB1 exerts dual effects on osteoclasts, directly by inducing differentiation through TLR4 and RAGE activation and indirectly by increasing pro-osteoclastogenic cytokine secretion from osteocytes.
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Affiliation(s)
- Hannah M Davis
- Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana Center for Musculoskeletal Health, Indianapolis, Indiana
| | - Sinai Valdez
- Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Leland Gomez
- Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Peter Malicky
- Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana
| | - Fletcher A White
- Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana.,Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana.,Roudebush Veterans Administration Medical Center, Indianapolis, Indiana
| | - Mark A Subler
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia
| | - Jolene J Windle
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia
| | - Joseph P Bidwell
- Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana Center for Musculoskeletal Health, Indianapolis, Indiana
| | - Angela Bruzzaniti
- Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana Center for Musculoskeletal Health, Indianapolis, Indiana.,Department of Biomedical and Applied Sciences, Indiana University School of Dentistry, Indianapolis, Indiana
| | - Lilian I Plotkin
- Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana Center for Musculoskeletal Health, Indianapolis, Indiana.,Roudebush Veterans Administration Medical Center, Indianapolis, Indiana
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25
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Allegra A, Musolino C, Pace E, Innao V, Di Salvo E, Ferraro M, Casciaro M, Spatari G, Tartarisco G, Allegra AG, Gangemi S. Evaluation of the AGE/sRAGE Axis in Patients with Multiple Myeloma. Antioxidants (Basel) 2019; 8:antiox8030055. [PMID: 30836666 PMCID: PMC6466542 DOI: 10.3390/antiox8030055] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 02/26/2019] [Accepted: 03/03/2019] [Indexed: 02/06/2023] Open
Abstract
Glycative stress influences tumor progression. The aim of the present study was to evaluate the advanced glycation end products/soluble receptor of advanced glycation end products (AGE/sRAGE) axis in patients with multiple myeloma (MM). Blood samples were taken from 19 patients affected by MM and from 16 sex-matched and age-matched healthy subjects. AGE and sRAGE axis were dosed in patients with MM and matched with controls. AGEs were measured by spectrofluorimetric methods. Blood samples for the determination of sRAGE were analyzed by ELISA. AGE levels were significantly reduced in patients with respect to controls. Instead, sRAGE was significantly elevated in patients affected by MM compared to healthy subjects. Moreover, we showed that there was a statistically significant difference in sRAGE according to the heavy and light chain. IgA lambda had significantly higher sRAGE values than IgA kappa, IgG kappa, and IgG Lambda MM patients. From our data emerges the role of the sRAGE/AGE axis in MM. Since AGE is a positive regulator of the activity of RAGE, circulating sRAGE concentrations may reflect RAGE expression and may be raised in parallel with serum AGE concentrations as a counter-system against AGE-caused tissue damage. Serum concentrations of AGE and sRAGE could therefore become potential therapeutic targets.
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Affiliation(s)
- Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 98125 Messina, Italy.
| | - Caterina Musolino
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 98125 Messina, Italy.
| | - Elisabetta Pace
- Institute of Biomedicine and Molecular Immunology "A. Monroy" (IBIM), National Research Council (CNR), 90146 Palermo, Italy.
| | - Vanessa Innao
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 98125 Messina, Italy.
| | - Eleonora Di Salvo
- National Research Council of Italy (CNR)-Institute of Applied Science and Intelligent System (ISASI), 98164 Messina, Italy.
| | - Maria Ferraro
- Institute of Biomedicine and Molecular Immunology "A. Monroy" (IBIM), National Research Council (CNR), 90146 Palermo, Italy.
| | - Marco Casciaro
- School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.
| | - Giovanna Spatari
- Department of Biomedical Sciences, Dental, Morphological and Functional Investigations, University of Messina, 98125 Messina, Italy.
| | - Gennaro Tartarisco
- National Research Council of Italy (CNR)-Institute of Applied Science and Intelligent System (ISASI), 98164 Messina, Italy.
| | - Andrea Gaetano Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 98125 Messina, Italy.
| | - Sebastiano Gangemi
- School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.
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Abstract
PURPOSE OF REVIEW The receptor for advanced glycation end products (RAGE) and several of its ligands have been implicated in the onset and progression of pathologies associated with aging, chronic inflammation, and cellular stress. In particular, the role of RAGE and its ligands in bone tissue during both physiological and pathological conditions has been investigated. However, the extent to which RAGE signaling regulates bone homeostasis and disease onset remains unclear. Further, RAGE effects in the different bone cells and whether these effects are cell-type specific is unknown. The objective of the current review is to describe the literature over RAGE signaling in skeletal biology as well as discuss the clinical potential of RAGE as a diagnostic and/or therapeutic target in bone disease. RECENT FINDINGS The role of RAGE and its ligands during skeletal homeostasis, tissue repair, and disease onset/progression is beginning to be uncovered. For example, detrimental effects of the RAGE ligands, advanced glycation end products (AGEs), have been identified for osteoblast viability/activity, while others have observed that low level AGE exposure stimulates osteoblast autophagy, which subsequently promotes viability and function. Similar findings have been reported with HMGB1, another RAGE ligand, in which high levels of the ligand are associated with osteoblast/osteocyte apoptosis, whereas low level/short-term administration stimulates osteoblast differentiation/bone formation and promotes fracture healing. Additionally, elevated levels of several RAGE ligands (AGEs, HMGB1, S100 proteins) induce osteoblast/osteocyte apoptosis and stimulate cytokine production, which is associated with increased osteoclast differentiation/activity. Conversely, direct RAGE-ligand exposure in osteoclasts may have inhibitory effects. These observations support a conclusion that elevated bone resorption observed in conditions of high circulating ligands and RAGE expression are due to actions on osteoblasts/osteocytes rather than direct actions on osteoclasts, although additional work is required to substantiate the observations. Recent studies have demonstrated that RAGE and its ligands play an important physiological role in the regulation of skeletal development, homeostasis, and repair/regeneration. Conversely, elevated levels of RAGE and its ligands are clearly related with various diseases associated with increased bone loss and fragility. However, despite the recent advancements in the field, many questions regarding RAGE and its ligands in skeletal biology remain unanswered.
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Affiliation(s)
- Lilian I Plotkin
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr., MS 5023, Indianapolis, IN, 46202, USA.
- Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
- Indiana Center for Musculoskeletal Health, Indianapolis, IN, USA.
| | - Alyson L Essex
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr., MS 5023, Indianapolis, IN, 46202, USA
- Indiana Center for Musculoskeletal Health, Indianapolis, IN, USA
| | - Hannah M Davis
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr., MS 5023, Indianapolis, IN, 46202, USA
- Indiana Center for Musculoskeletal Health, Indianapolis, IN, USA
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27
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Pitocco D, Scavone G, Di Leo M, Vitiello R, Rizzi A, Tartaglione L, Costantini F, Flex A, Galli M, Caputo S, Ghirlanda G, Pontecorvi A. Charcot Neuroarthropathy: From the Laboratory to the Bedside. Curr Diabetes Rev 2019; 16:62-72. [PMID: 31057120 DOI: 10.2174/1573399815666190502121945] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 03/26/2019] [Accepted: 04/17/2019] [Indexed: 01/11/2023]
Abstract
BACKGROUND The diabetic Charcot foot syndrome is a serious and potentially limbthreatening lower-extremity complication of diabetes. INTRODUCTION The present review provides a concise account of the advances made over the last twentyfive years in understanding the pathogenesis and management of Charcot neuroarthropathy (CN). METHODS In this study, the widely known pathogenetic mechanisms underpinning CN are brought into focus, particularly the role of RANKL/RANK/OPG system and advanced glycation end production in the pathogenesis of CN. Furthermore, other potential triggering factors, namely nitric oxide, endothelial dysfunction, macro calcifications and body weight that influence CN have also been discussed. RESULTS The wide range of diagnostic tools available to clinicians for accurate staging of this pathology has been examined, particularly radiological and nuclear medicine imaging. Additionally, the difficult differential diagnosis between osteomyelitis and CN is also elucidated. CONCLUSION The review concludes with the comprehensive summary of the major promising therapeutic strategies, including conservative treatment involving orthopedic devices, pharmacological approach, and the most common surgical techniques currently employed in the diagnosis and treatment of this acute disease.
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Affiliation(s)
- Dario Pitocco
- Diabetes Care Unit, Institute of Endocrinology, Catholic University of Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Giuseppe Scavone
- Diabetes Care Unit, Institute of Endocrinology, Catholic University of Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Mauro Di Leo
- Diabetes Care Unit, Institute of Endocrinology, Catholic University of Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Raffaele Vitiello
- Diabetes Care Unit, Institute of Endocrinology, Catholic University of Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Alessandro Rizzi
- Diabetes Care Unit, Institute of Endocrinology, Catholic University of Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Linda Tartaglione
- Diabetes Care Unit, Institute of Endocrinology, Catholic University of Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Federica Costantini
- Diabetes Care Unit, Institute of Endocrinology, Catholic University of Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Andrea Flex
- Institute of Internal Medicine, Catholic University of Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Marco Galli
- Institute of Orthopedic Surgery, Catholic University of Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Salvatore Caputo
- Diabetes Care Unit, Institute of Endocrinology, Catholic University of Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Giovanni Ghirlanda
- Diabetes Care Unit, Institute of Endocrinology, Catholic University of Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Alfredo Pontecorvi
- Diabetes Care Unit, Institute of Endocrinology, Catholic University of Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
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Hu Y, Tan LJ, Chen XD, Greenbaum J, Deng HW. Identification of novel variants associated with osteoporosis, type 2 diabetes and potentially pleiotropic loci using pleiotropic cFDR method. Bone 2018; 117:6-14. [PMID: 30172742 PMCID: PMC6364698 DOI: 10.1016/j.bone.2018.08.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 08/27/2018] [Accepted: 08/29/2018] [Indexed: 12/16/2022]
Abstract
AIMS Clinical and epidemiological findings point to an association between type 2 diabetes (T2D) and osteoporosis. Genome-wide association studies (GWASs) have been fruitful in identifying some loci potentially associated with osteoporosis and T2D respectively. However, the total genetic variance for each of these two diseases and the shared genetic determination between them are largely unknown. The aim of this study was to identify novel genetic variants for osteoporosis and/or T2D. METHODS First, using a pleiotropic conditional false discovery rate (cFDR) method, we analyzed two GWAS summary data of femoral neck bone mineral density (FN_BMD, n = 53,236) and T2D (n = 159,208) to identify novel shared genetic loci. FN_BMD is an important risk factor for osteoporosis. Next, to explore the potential functions of the identified potential pleiotropic genes, differential expression analysis was performed for them in monocytes and peripheral blood mononuclear cells (PBMCs) as these cells are relevant to the etiology of osteoporosis and/or T2D. Further, weighted gene co-expression analysis (WGCNA) was conducted to identify functional connections between novel pleiotropic genes and known osteoporosis/T2D susceptibility genes by using transcriptomic expression datasets in bone biopsies (E-MEXP-1618) and pancreatic islets (GSE50397). Finally, multi-trait fine mapping for the detected pleiotropic risk loci were conducted to identify the SNPs that have the highest probability of being causal for both FN_BMD and T2D. RESULTS We identified 27 significant SNPs with cFDR<0.05 for FN_BMD and 61 SNPs for T2D respectively. Four loci, rs7068487 (PLEKHA1), rs10885421 (TCF7L2), rs944082 (GNG12-AS1 (WLS)) and rs2065929 (PIFO||PGCP1), were found to be potentially pleiotropic and shared between FN_BMD and T2D (ccFDR<0.05). PLEKHA1 was found differentially expressed in circulating monocytes between high and low BMD subjects, and PBMCs between diabetic and non-diabetic conditions. WGCNA showed that PLEKHA1 and TCF7L2 were interconnected with multiple osteoporosis and T2D associated genes in bone biopsy and pancreatic islets, such as JAG, EN1 and CPE. Fine mapping showed that rs11200594 was a potentially causal variant in the locus of PLEKHA1. rs11200594 is also an eQTL of PLEKHA1 in multiple tissue (e.g. peripheral blood cells, adipose and ovary) and is in strong LD with a number of functional variants. CONCLUSIONS Four potential pleiotropic loci were identified for shared genetic determination of osteoporosis and T2D. Our study highlights PLEKHA1 as an important potentially pleiotropic gene. The findings may help us gain a better understanding of the shared genetic determination between these two important disorders.
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Affiliation(s)
- Yuan Hu
- Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China
| | - Li-Jun Tan
- Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China
| | - Xiang-Ding Chen
- Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China
| | - Jonathan Greenbaum
- School of Basic Medical Sciences, Central South University, Changsha, Hunan 410013, China
| | - Hong-Wen Deng
- Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China; School of Basic Medical Sciences, Central South University, Changsha, Hunan 410013, China; Center of Bioinformatics and Genomics, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA.
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29
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Jia T, Wang YN, Zhang D, Xu X. 1α,25-dihydroxyvitamin D3 promotes osseointegration of titanium implant via downregulating AGEs/RAGE pathway in T2DM. Endocr Connect 2018; 7:1186-1195. [PMID: 30352411 PMCID: PMC6215803 DOI: 10.1530/ec-18-0241] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 09/25/2018] [Indexed: 01/22/2023]
Abstract
Diabetes-induced advanced glycation end products (AGEs) overproduction would result in compromised osseointegration of titanium implant and high rate of implantation failure. 1α,25-dihydroxyvitamin D3 (1,25VD3) plays a vital role in osteogenesis, whereas its effects on the osseointegration and the underlying mechanism are unclear. The purpose of this study was to investigate that 1,25VD3 might promote the defensive ability of osseointegration through suppressing AGEs/RAGE in type 2 diabetes mellitus. In animal study, streptozotocin-induced diabetic rats accepted implant surgery, with or without 1,25VD3 intervention for 12 weeks. After killing, the serum AGEs level, bone microarchitecture and biomechanical index of rats were measured systematically. In vitro study, osteoblasts differentiation capacity was analyzed by alizarin red staining, alkaline phosphatase assay and Western blotting, after treatment with BSA, AGEs, AGEs with RAGE inhibitor and AGEs with 1,25VD3. And the expression of RAGE protein was detected to explore the mechanism. Results showed that 1,25VD3 could reverse the impaired osseointegration and mechanical strength, which possibly resulted from the increased AGEs. Moreover, 1,25VD3 could ameliorate AGEs-induced damage of cell osteogenic differentiation, as well as downregulating the RAGE expression. These data may provide a theoretical basis that 1,25VD3 could work as an adjuvant treatment against poor osseointegration in patients with type 2 diabetes mellitus.
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Affiliation(s)
- Tingting Jia
- Department of ImplantologySchool of Stomatology, Shandong University, Jinan, People’s Republic of China
- Shandong Provincial Key Laboratory of Oral Tissue RegenerationJinan, People’s Republic of China
| | - Ya-nan Wang
- Department of ImplantologySchool of Stomatology, Shandong University, Jinan, People’s Republic of China
- Shandong Provincial Key Laboratory of Oral Tissue RegenerationJinan, People’s Republic of China
| | - Dongjiao Zhang
- Department of ImplantologySchool of Stomatology, Shandong University, Jinan, People’s Republic of China
- Shandong Provincial Key Laboratory of Oral Tissue RegenerationJinan, People’s Republic of China
| | - Xin Xu
- Department of ImplantologySchool of Stomatology, Shandong University, Jinan, People’s Republic of China
- Shandong Provincial Key Laboratory of Oral Tissue RegenerationJinan, People’s Republic of China
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Hu H, Jiang H, Zhu L, Wu X, Han C. Accumulation of Advanced Glycation Endproducts and Subclinical Inflammation in Deep Tissues of Adult Patients With and Without Diabetes. Can J Diabetes 2018; 42:525-532.e4. [DOI: 10.1016/j.jcjd.2018.01.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 01/03/2018] [Indexed: 01/22/2023]
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Valenzuela A, Guerra-Hernández E, Rufián-Henares JÁ, Márquez-Ruiz AB, Hougen HP, García-Villanova B. Differences in non-enzymatic glycation products in human dentine and clavicle: changes with aging. Int J Legal Med 2018; 132:1749-1758. [DOI: 10.1007/s00414-018-1908-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 07/26/2018] [Indexed: 01/22/2023]
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In vitro assessment of ribose modified two-step etch-and-rinse dentine adhesive. Dent Mater 2018; 34:1175-1187. [PMID: 29779627 DOI: 10.1016/j.dental.2018.05.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 04/19/2018] [Accepted: 05/02/2018] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Collagen fibrils aid in anchoring resin composite restorations to the dentine substrate. The aim of the study was to investigate effect of non-enzymatic glycation on bond strength and durability of demineralized dentine specimens in a modified two-step etch-and-rinse dentine adhesive. METHODS Dentine surfaces were etched with 37% phosphoric acid, bonded with respective in vitro ethanol and acetone adhesives modified with (m/m, 0, 1%, 2% and 3% ribose), restored with restorative composite-resin, and sectioned into resin-dentine slabs and beams to be stored for 24h or 12 months in artificial saliva. Bond-strength testing was performed with bond failure analysis. Pentosidine assay was performed on demineralized ribose modified dentine specimens with HPLC sensitive fluorescent detection. The structural variations of ribose-modified dentine were analysed using TEM and human dental pulpal cells were used for cell viability. Three-point bending test of ribose-modified dentine beams were performed and depth of penetration of adhesives evaluated with micro-Raman spectroscopy. The MMP-2 and cathepsin K activities in ribose-treated dentine powder were also quantified using ELISA. Bond strength data was expressed using two-way ANOVA followed by Tukey's test. Paired T tests were used to analyse the specimens for pentosidine crosslinks. The modulus of elasticity and dentinal MMP-2 and cathepsin K concentrations was separately analyzed using one-way ANOVA. RESULTS The incorporation of RB in the experimental two-step etch-and-rinse adhesive at 1% improved the adhesive bond strength without adversely affecting the degree of polymerisation. The newly developed adhesive increases the resistance of dentine collagen to degradation by inhibiting endogenous matrix metalloproteinases and cysteine cathepsins. The application of RB to acid-etched dentine helps maintain the mechanical properties. SIGNIFICANCE The incorporation of 1%RB can be considered as a potential candidate stabilizing resin dentine bond.
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Choi YJ, Ock SY, Jin Y, Lee JS, Kim SH, Chung YS. Urinary Pentosidine levels negatively associates with trabecular bone scores in patients with type 2 diabetes mellitus. Osteoporos Int 2018; 29:907-915. [PMID: 29322222 DOI: 10.1007/s00198-017-4359-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 12/18/2017] [Indexed: 12/27/2022]
Abstract
UNLABELLED Pentosidine levels were higher in diabetic patients with vertebral fractures. Trabecular bone scores were negatively associated with pentosidine levels in diabetic patients only. Our results provide further evidence that AGEs are associated with the pathogenesis of bone fragility in patients with T2DM. INTRODUCTION Type 2 diabetes mellitus (T2DM) is associated with fracture risk. Pentosidine, an advanced glycation end product (AGE), is associated with prevalent vertebral fractures (VFs) in patients with T2DM. Trabecular bone score (TBS) has been proposed as an index of bone microarchitecture associated with bone quality. This study evaluated the associations of urine pentosidine and TBS in T2DM and non-T2DM groups. METHODS A total of 112 T2DM patients and 62 non-T2DM subjects were enrolled. TBS was calculated using TBS insight® software (version 2.1). Pentosidine levels were measured using high-performance liquid chromatography method. We compared the BMD, TBS, and pentosidine levels between those with and without VFs with or without adjustment for age and sex. The association with TBS, lumbar spine BMD, and pentosidine levels were also evaluated in both T2DM and non-T2DM groups. RESULTS Pentosidine levels were significantly higher in T2DM patients with VFs. TBSs were significantly lower in patients with T2DM and VFs. In non-diabetic patients, there were no significant differences in TBS and pentosidine levels for those with and without VFs after adjustment for age and sex. Pentosidine levels were negatively associated with TBS only in patients with T2DM. In multivariate stepwise regression analysis, pentosidine levels were significantly associated with TBS in patients with T2DM. CONCLUSIONS TBS and pentosidine could be used as a method to assess bone quality to identify T2DM patients at risk of VFs. Our results also provide further evidence that AGEs are associated with the pathogenesis of bone fragility in patients with T2DM.
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Affiliation(s)
- Y J Choi
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 World cup-ro, Suwon, 16499, South Korea
| | - S Y Ock
- Department of Endocrinology and Metabolism, Kosin University School of Medicine, Busan, South Korea
| | - Y Jin
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 World cup-ro, Suwon, 16499, South Korea
| | - J S Lee
- College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon, South Korea
| | - S H Kim
- College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon, South Korea
| | - Y -S Chung
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 World cup-ro, Suwon, 16499, South Korea.
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Bone Metabolism and Fracture Risk in Diabetes Mellitus. J ASEAN Fed Endocr Soc 2017; 32:90-99. [PMID: 33442091 PMCID: PMC7784240 DOI: 10.15605/jafes.032.02.14] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 09/30/2017] [Indexed: 01/14/2023] Open
Abstract
Individuals with Type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are at increased risk for fragility fractures. Bone mineral density (BMD) is decreased in T1DM but often normal or even elevated in T2DM when compared with age-matched non-DM populations. However, bone turnover is decreased in both T1DM and T2DM. The pathophysiologic mechanisms leading to bone fragility is multifactorial, and potentially leads to reduced bone formation, altered bone microstructure and decreased bone strength. Interestingly, different antidiabetic treatments may influence fracture risk due to effects on glycemic control, triggering of hypoglycemic events or osteoblastogenesis.
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Attia T, Woodside M, Minhas G, Lu XZ, Josey DS, Burrow T, Grynpas M, Willett TL. Development of a novel method for the strengthening and toughening of irradiation-sterilized bone allografts. Cell Tissue Bank 2017; 18:323-334. [PMID: 28560495 DOI: 10.1007/s10561-017-9634-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 05/26/2017] [Indexed: 01/22/2023]
Abstract
Reconstruction of large skeletal defects is a significant and challenging issue. Bone allografts are often used for such reconstructions. However, sterilizing bone allografts by using γ-irradiation, damages collagen and causes the bone to become weak, brittle and less fatigue resistant. In a previous study, we successfully protected the mechanical properties of human cortical bone by conducting a pre-treatment with ribose, a natural and biocompatible agent. This study focuses on examining possible mechanisms by which ribose might protect the bone. We examined the mechanical properties, crosslinking, connectivity and free radical scavenging potentials of the ribose treatment. Human cortical bone beams were treated with varying concentration of ribose (0.06-1.2 M) and γ-irradiation before testing them in 3-point bending. The connectivity and amounts of crosslinking were determined with Hydrothermal-Isometric-Tension testing and High-Performance-Liquid-Chromatography, respectively. The free radical content was measured using Electron Paramagnetic Resonance. Ribose pre-treatment improved the mechanical properties of irradiation sterilized human bone in a pre-treatment concentration-dependent manner. The 1.2 M pre-treatment provided >100% of ultimate strength of normal controls and protected 76% of the work-to-fracture (toughness) lost in the irradiated controls. Similarly, the ribose pre-treatment improved the thermo-mechanical properties of irradiation-sterilized human bone collagen in a concentration-dependent manner. Greater free radical content and pentosidine content were modified in the ribose treated bone. This study shows that the mechanical properties of irradiation-sterilized cortical bone allografts can be protected by incubating the bone in a ribose solution prior to irradiation.
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Affiliation(s)
- Tarik Attia
- Musculoskeletal Research Laboratory, Mount Sinai Hospital - Lunenfeld Tanenbaum Research Institute, Toronto, ON, Canada.,Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Mitchell Woodside
- Musculoskeletal Research Laboratory, Mount Sinai Hospital - Lunenfeld Tanenbaum Research Institute, Toronto, ON, Canada
| | - Gagan Minhas
- Musculoskeletal Research Laboratory, Mount Sinai Hospital - Lunenfeld Tanenbaum Research Institute, Toronto, ON, Canada
| | - Xing Ze Lu
- Musculoskeletal Research Laboratory, Mount Sinai Hospital - Lunenfeld Tanenbaum Research Institute, Toronto, ON, Canada
| | - David S Josey
- Musculoskeletal Research Laboratory, Mount Sinai Hospital - Lunenfeld Tanenbaum Research Institute, Toronto, ON, Canada
| | - Timothy Burrow
- Department of Chemistry, University of Toronto, Toronto, ON, Canada
| | - Marc Grynpas
- Musculoskeletal Research Laboratory, Mount Sinai Hospital - Lunenfeld Tanenbaum Research Institute, Toronto, ON, Canada.,Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Thomas L Willett
- Biomedical Engineering Program, Department of Systems Design Engineering, University of Waterloo, 200 University Avenue West, Waterloo, ON, Canada.
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Pernelle K, Imbert L, Bosser C, Auregan JC, Cruel M, Ogier A, Jurdic P, Hoc T. Microscale mechanical and mineral heterogeneity of human cortical bone governs osteoclast activity. Bone 2017; 94:42-49. [PMID: 27725316 DOI: 10.1016/j.bone.2016.10.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 09/22/2016] [Accepted: 10/06/2016] [Indexed: 01/22/2023]
Abstract
Human cortical bone permanently remodels itself resulting in a haversian microstructure with heterogeneous mechanical and mineral properties. Remodeling is carried out by a subtle equilibrium between bone formation by osteoblasts and bone degradation by osteoclasts. The mechanisms regulating osteoclast activity were studied using easy access supports whose homogeneous microstructures differ from human bone microstructure. In the current study, we show that human osteoclasts resorb human cortical bone non-randomly with respect to this specific human bone microstructural heterogeneity. The characterization of this new resorption profile demonstrates that osteoclasts preferentially resorb particular osteons that have weak mechanical properties and mineral contents and that contain small hydroxyapatite crystals with a high carbonate content. Therefore, the influence of human bone microstructure heterogeneity on osteoclast activity could be a key parameter for osteoclast behaviour, for both in vitro and clinical studies.
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Affiliation(s)
- K Pernelle
- LTDS UMR CNRS 5513, Ecole Centrale Lyon, 36 avenue Guy de Collongue, 69134 Ecully, France; Institut de Génomique Fonctionnelle de Lyon UMR5242, Université de Lyon, CNRS, Ecole Normale Supérieure de Lyon, 46, allée d'Italie, 69364 Lyon cedex 07, France
| | - L Imbert
- LTDS UMR CNRS 5513, Ecole Centrale Lyon, 36 avenue Guy de Collongue, 69134 Ecully, France; Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States
| | - C Bosser
- LTDS UMR CNRS 5513, Ecole Centrale Lyon, 36 avenue Guy de Collongue, 69134 Ecully, France
| | - J-C Auregan
- LTDS UMR CNRS 5513, Ecole Centrale Lyon, 36 avenue Guy de Collongue, 69134 Ecully, France; Département de l'Orthopédie pédiatrique, Necker-Hopital des enfants Malades, AP-HP, Paris Descartes, 145 rue de Sèvres, 75014 Paris, France
| | - M Cruel
- LTDS UMR CNRS 5513, Ecole Centrale Lyon, 36 avenue Guy de Collongue, 69134 Ecully, France
| | - A Ogier
- LTDS UMR CNRS 5513, Ecole Centrale Lyon, 36 avenue Guy de Collongue, 69134 Ecully, France
| | - P Jurdic
- Institut de Génomique Fonctionnelle de Lyon UMR5242, Université de Lyon, CNRS, Ecole Normale Supérieure de Lyon, 46, allée d'Italie, 69364 Lyon cedex 07, France
| | - T Hoc
- LTDS UMR CNRS 5513, Ecole Centrale Lyon, 36 avenue Guy de Collongue, 69134 Ecully, France.
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Abstract
Diabetic patients have a higher fracture risk than expected by their bone mineral density (BMD). Poor bone quality is the most suitable and explainable cause for the elevated fracture risk in this population. Advanced glycation end products (AGEs), which are diverse compounds generated via a non-enzymatic reaction between reducing sugars and amine residues, physically affect the properties of the bone material, one of a component of bone quality, through their accumulation in the bone collagen fibers. On the other hand, these compounds biologically act as agonists for these receptors for AGEs (RAGE) and suppress bone metabolism. The concentrations of AGEs and endogenous secretory RAGE, which acts as a "decoy receptor" that inhibits the AGEs-RAGE signaling axis, are associated with fracture risk in a BMD-independent manner. AGEs are closely associated with the pathogenesis of this unique clinical manifestation through physical and biological mechanisms in patients with diabetes mellitus.
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Affiliation(s)
- Masahiro Yamamoto
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501 Japan
| | - Toshitsugu Sugimoto
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501 Japan
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Campbell GM, Tiwari S, Picke AK, Hofbauer C, Rauner M, Morlock MM, Hofbauer LC, Glüer CC. Effects of insulin therapy on porosity, non-enzymatic glycation and mechanical competence in the bone of rats with type 2 diabetes mellitus. Bone 2016; 91:186-93. [PMID: 27497735 DOI: 10.1016/j.bone.2016.08.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 08/01/2016] [Accepted: 08/02/2016] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and optimal treatment strategies remain unclear. We studied the effects of diabetes and insulin therapy on non-enzymatic glycation (NEG), cortical porosity (Ct.Po) and biomechanics of the bone tissue in Zucker Diabetic Fatty (ZDF) rats. Eleven-week old ZDF diabetic and non-diabetic rats were given insulin to achieve glycaemic control or vehicle seven days per week over twelve weeks (insulin dose adapted individually 0.5 international units (IU) at week 1 to 13.0IU at week 12). The right femora were excised, micro-CT scanned, and tested in 3-point bending to measure biomechanics. NEG of the midshaft was determined from bulk fluorescence. Diabetes led to increased NEG (+50.1%, p=0.001) and Ct.Po (+22.9%, p=0.004), as well as to reduced mechanical competence (max. stress: -14.2%, p=0.041, toughness: -29.7%, p=0.016) in the bone tissue. NEG and Ct.Po both correlated positively to serum glucose (NEG: R(2)=0.41, p<0.001, Ct.Po: R(2)=0.34, p=0.003) and HbA1c (NEG: R(2)=0.42, p<0.001, Ct.Po: R(2)=0.28, p=0.008) levels, while NEG correlated negatively with bone biomechanics (elastic modulus: R(2)=0.21, p=0.023, yield stress: R(2)=0.17, p=0.047). Twelve weeks of insulin therapy had no significant effect on NEG or Ct.Po, and was unable to improve the mechanical competence of the bone tissue. A reduction of mechanical competence was observed in the bone tissue of the diabetic rats, which was explained in part by increased collagen NEG. Twelve weeks of insulin therapy did not alter NEG, Ct.Po or bone biomechanics. However, significant correlations between NEG and serum glucose and HbA1c were observed, both of which were reduced with insulin therapy. This suggests that a longer duration of insulin therapy may be required to reduce the NEG of the bone collagen and restore the mechanical competence of diabetic bone.
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Affiliation(s)
- G M Campbell
- Section Biomedical Imaging, Department of Radiology and Neurology, University Hospital Schleswig-Holstein, Campus Kiel, Germany; Institute of Biomechanics, TUHH Hamburg University of Technology, Hamburg, Germany.
| | - S Tiwari
- Section Biomedical Imaging, Department of Radiology and Neurology, University Hospital Schleswig-Holstein, Campus Kiel, Germany
| | - A-K Picke
- Department of Medicine III, Technische Universität Dresden Medical Center, Dresden, Germany
| | - C Hofbauer
- Department of Orthopedics, Technische Universität Dresden Medical Center, Dresden, Germany
| | - M Rauner
- Department of Medicine III, Technische Universität Dresden Medical Center, Dresden, Germany
| | - M M Morlock
- Institute of Biomechanics, TUHH Hamburg University of Technology, Hamburg, Germany
| | - L C Hofbauer
- Department of Medicine III, Technische Universität Dresden Medical Center, Dresden, Germany; Center for Regenerative Therapies Dresden, Germany
| | - C-C Glüer
- Section Biomedical Imaging, Department of Radiology and Neurology, University Hospital Schleswig-Holstein, Campus Kiel, Germany
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Heilmeier U, Cheng K, Pasco C, Parrish R, Nirody J, Patsch JM, Zhang CA, Joseph GB, Burghardt AJ, Schwartz AV, Link TM, Kazakia G. Cortical bone laminar analysis reveals increased midcortical and periosteal porosity in type 2 diabetic postmenopausal women with history of fragility fractures compared to fracture-free diabetics. Osteoporos Int 2016; 27:2791-2802. [PMID: 27154435 PMCID: PMC6687459 DOI: 10.1007/s00198-016-3614-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 04/20/2016] [Indexed: 02/08/2023]
Abstract
UNLABELLED We investigated the characteristics and spatial distribution of cortical bone pores in postmenopausal women with type 2 diabetes (T2D). High porosity in the midcortical and periosteal layers in T2D subjects with fragility fractures suggests that these cortical zones might be particularly susceptible to T2D-induced toxicity and may reflect cortical microangiopathy. INTRODUCTION Elevated cortical porosity is regarded as one of the main contributors to the high skeletal fragility in T2D. However, to date, it remains unclear if diabetic cortical porosity results from vascular cortical changes or from an expansion in bone marrow space. Here, we used a novel cortical laminar analysis technique to investigate the characteristics and spatial radial distribution of cortical pores in a T2D group with prior history of fragility fractures (DMFx, assigned high-risk group) and a fracture-free T2D group (DM, assigned low-risk group) and to compare their results to non-diabetic controls with (Fx) and without fragility fractures (Co). METHODS Eighty postmenopausal women (n = 20/group) underwent high-resolution peripheral quantitative computed tomography (HR-pQCT) of the distal tibia and radius. Cortical bone was divided into three layers of equal width including an endosteal, midcortical, and periosteal layer. Within each layer, total pore area (TPA), total pore number (TPN), and average pore area (APA) were calculated. Statistical analysis employed Mann-Whitney tests and ANOVA with post hoc tests. RESULTS Compared to the DM group, DMFx subjects exhibited +90 to +365 % elevated global porosity (p = 0.001). Cortical laminar analysis revealed that this increased porosity was for both skeletal sites confined to the midcortical layer, followed by the periosteal layer (midcortical +1327 % TPA, p ≤ 0.001, periosteal +634 % TPA, p = 0.002), and was associated in both layers and skeletal sites with high TPN (+430 % TPN, p < 0.001) and high APA (+71.5 % APA, p < 0.001). CONCLUSION High porosity in the midcortical and periosteal layers in the high-risk T2D group suggests that these cortical zones might be particularly susceptible to T2D-induced toxicity and may reflect cortical microangiopathy.
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Affiliation(s)
- U Heilmeier
- Musculoskeletal Quantitative Imaging Research Group, Department of Radiology & Biomedical Imaging, University of California San Francisco, 185 Berry Street, San Francisco, CA, 94158, USA.
| | - K Cheng
- Department of Bioengineering, University of California Berkeley, 306 Stanley Hall, Berkeley, CA, 94720, USA
| | - C Pasco
- Department of Bioengineering, University of California Berkeley, 306 Stanley Hall, Berkeley, CA, 94720, USA
| | - R Parrish
- Department of Bioengineering, University of California Berkeley, 306 Stanley Hall, Berkeley, CA, 94720, USA
| | - J Nirody
- Biophysics Graduate Group, University of California Berkeley, 574 Stanley Hall, MC 3220, Berkeley, CA, 94720, USA
| | - J M Patsch
- Musculoskeletal Quantitative Imaging Research Group, Department of Radiology & Biomedical Imaging, University of California San Francisco, 185 Berry Street, San Francisco, CA, 94158, USA
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - C A Zhang
- Department of Epidemiology and Biostatistics, University of California San Francisco, 550 16th Street, San Francisco, CA, 94158, USA
| | - G B Joseph
- Musculoskeletal Quantitative Imaging Research Group, Department of Radiology & Biomedical Imaging, University of California San Francisco, 185 Berry Street, San Francisco, CA, 94158, USA
| | - A J Burghardt
- Musculoskeletal Quantitative Imaging Research Group, Department of Radiology & Biomedical Imaging, University of California San Francisco, 185 Berry Street, San Francisco, CA, 94158, USA
| | - A V Schwartz
- Department of Epidemiology and Biostatistics, University of California San Francisco, 550 16th Street, San Francisco, CA, 94158, USA
| | - T M Link
- Musculoskeletal Quantitative Imaging Research Group, Department of Radiology & Biomedical Imaging, University of California San Francisco, 185 Berry Street, San Francisco, CA, 94158, USA
| | - G Kazakia
- Musculoskeletal Quantitative Imaging Research Group, Department of Radiology & Biomedical Imaging, University of California San Francisco, 185 Berry Street, San Francisco, CA, 94158, USA
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Osterhoff G, Morgan EF, Shefelbine SJ, Karim L, McNamara LM, Augat P. Bone mechanical properties and changes with osteoporosis. Injury 2016; 47 Suppl 2:S11-20. [PMID: 27338221 PMCID: PMC4955555 DOI: 10.1016/s0020-1383(16)47003-8] [Citation(s) in RCA: 318] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This review will define the role of collagen and within-bone heterogeneity and elaborate the importance of trabecular and cortical architecture with regard to their effect on the mechanical strength of bone. For each of these factors, the changes seen with osteoporosis and ageing will be described and how they can compromise strength and eventually lead to bone fragility.
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Affiliation(s)
- Georg Osterhoff
- Division of Orthopaedic Trauma, Department of Orthopaedic Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Elise F. Morgan
- Department of Mechanical Engineering, Boston University, Boston, MA 02215, USA
| | - Sandra J. Shefelbine
- Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, USA
| | - Lamya Karim
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center and Department of Orthopedic Surgery, Harvard Medical School, Boston, MA 02215, USA
| | - Laoise M. McNamara
- Centre for Biomechanics Research (BMEC), Department of Biomedical Engineering, NUI Galway, Galway, Republic of Ireland,National Centre for Biomedical Engineering Science (NCBES), NUI Galway, Galway, Republic of Ireland
| | - Peter Augat
- Institute of Biomechanics, Trauma Center Murnau, Murnau, Germany and Paracelsus Medical University Salzburg, Salzburg, Austria,Corresponding author at: Institute of Biomechanics, Berufsgenossenschaftliche Unfallklinik, Murnau Prof.-Kuentscher-Str. 8, D-82418 Murnau am Staffelsee, Germany. Tel.: +49 8841 484563; fax: +49 8841 484573. (P. Augat)
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Abstract
Diabetes is one of the main economic burdens in health care, which threatens to worsen dramatically if prevalence forecasts are correct. What makes diabetes harmful is the multi-organ distribution of its microvascular and macrovascular complications. Regenerative medicine with cellular therapy could be the dam against life-threatening or life-altering complications. Bone marrow-derived stem cells are putative candidates to achieve this goal. Unfortunately, the bone marrow itself is affected by diabetes, as it can develop a microangiopathy and neuropathy similar to other body tissues. Neuropathy leads to impaired stem cell mobilization from marrow, the so-called mobilopathy. Here, we review the role of bone marrow-derived stem cells in diabetes: how they are affected by compromised bone marrow integrity, how they contribute to other diabetic complications, and how they can be used as a treatment for these. Eventually, we suggest new tactics to optimize stem cell therapy.
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Affiliation(s)
- Giuseppe Mangialardi
- Bristol Heart Institute, University of Bristol, Level 7, Bristol Royal Infirmary, Upper Maudlin Street, Bristol, BS28HW UK
| | - Paolo Madeddu
- Bristol Heart Institute, University of Bristol, Level 7, Bristol Royal Infirmary, Upper Maudlin Street, Bristol, BS28HW UK
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42
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Li W, Ling W, Teng X, Quan C, Cai S, Hu S. Effect of advanced glycation end products, extracellular matrix metalloproteinase inducer and matrix metalloproteinases on type-I collagen metabolism. Biomed Rep 2016; 4:691-693. [PMID: 27284408 PMCID: PMC4887805 DOI: 10.3892/br.2016.641] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 03/23/2016] [Indexed: 12/14/2022] Open
Abstract
The aim of the study was to examine the association among advanced glycation end products (AGEs), extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase (MMPs), and investigate whether AGEs affect type I collagen (COL-I) through EMMPRIN or MMPs. A co-culture system with the osteoblast-like cells (MC3T3E1) and mouse RAW264.7 cells was employed to examine the effects of AGE-bovine serum albumin (BSA) (50 mg/l), EMMPRIN antibody (5 mg/l) and AGE-BSA+EMMPRIN antibody separately on COL-I expression for 24 h. Culture media were analyzed for the content of COL-I by ELISA. The effect of different concentrations of AGE-BSA (0, 50, 100, 200 and 400 mg/l) for 24 h was assessed on COL-I levels. Finally, semiquantitative RT-PCR was used to detect the osteoblast COL-I mRNA expression and MMP-2 and MMP-9's PMAO were also measured in the culture medium. COL-I content in the culture medium decreased significantly following treatment with AGE-BSA (P<0.05). EMMPRIN antibody increased COL-I content (P<0.05). EMMPRIN antibody+AGE-BSA increased COL-I significantly (P<0.05). Different concentrations of AGE-BSA increased COL-I mRNA expression significantly compared with the control group (P<0.05), and were enhanced with increasing AGE-BSA concentration (P<0.05). Also MMP-2 and MMP-9 secretion increased significantly (P<0.05), with the increasing AGE-BSA concentration. In conclusion, an increase in AGE levels in vitro stimulates the secretion of EMMPRIN/MMPs, promotes the degradation of COL-I and reduces bone strength.
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Affiliation(s)
- Wang Li
- Department of Clinical Laboratory, Xuzhou First People's Hospital, Xuzhou, Jiangsu 221002, P.R. China
| | - Wang Ling
- Department of Clinical Laboratory, Xuzhou First People's Hospital, Xuzhou, Jiangsu 221002, P.R. China
| | - Xiaomei Teng
- Department of Clinical Laboratory, Xuzhou First People's Hospital, Xuzhou, Jiangsu 221002, P.R. China
| | - Cuixia Quan
- Department of Clinical Laboratory, Xuzhou First People's Hospital, Xuzhou, Jiangsu 221002, P.R. China
| | - Shengnan Cai
- Department of Clinical Laboratory, Xuzhou First People's Hospital, Xuzhou, Jiangsu 221002, P.R. China
| | - Shuqun Hu
- Teaching and Research Section of Biochemistry, Xuzhou Medical College, Xuzhou, Jiangsu 221004, P.R. China
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43
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Li Z, Li C, Zhou Y, Chen W, Luo G, Zhang Z, Wang H, Zhang Y, Xu D, Sheng P. Advanced glycation end products biphasically modulate bone resorption in osteoclast-like cells. Am J Physiol Endocrinol Metab 2016; 310:E355-66. [PMID: 26670486 DOI: 10.1152/ajpendo.00309.2015] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 12/14/2015] [Indexed: 01/22/2023]
Abstract
Advanced glycation end products (AGEs) disturb bone remodeling during aging, and this process is accelerated in diabetes. However, their role in modulation of osteoclast-induced bone resorption is controversial, with some studies indicating that AGEs enhance bone resorption and others showing the opposite effect. We determined whether AGEs present at different stages of osteoclast differentiation affect bone resorption differently. Based on increased levels of tartrate-resistant acid phosphatase (TRAP) and cathepsin K (CTSK), we identified day 4 of induction as the dividing time of cell fusion stage and mature stage in RAW264.7 cell-derived osteoclast-like cells (OCLs). AGE-modified BSA (50-400 μg/ml) or control BSA (100 μg/ml) was then added at the beginning of each stage. Results showed that the presence of AGEs at the cell fusion stage reduced pit numbers, resorption area, and CTSK expression. Moreover, expression of receptor activator of nuclear factor-κB (RANK) as well as the number of TRAP-positive cells, nuclei per OCL, actin rings, and podosomes also decreased. However, the presence of AGEs at the mature stage enlarged the resorption area markedly and increased pit numbers slightly. Intriguingly, only the number of nuclei per OCL and podosomes increased. These data indicate that AGEs biphasically modulate bone resorption activity of OCLs in a differentiation stage-dependent manner. AGEs at the cell fusion stage reduce bone resorption dramatically, mainly via suppression of RANK expression in osteoclast precursors, whereas AGEs at the mature stage enhance bone resorption slightly, most likely by increasing the number of podosomes in mature OCLs.
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Affiliation(s)
- Ziqing Li
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; and
| | - Chaohong Li
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yuhuan Zhou
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Weishen Chen
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; and
| | - Guotian Luo
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; and
| | - Ziji Zhang
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; and
| | - Haixing Wang
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; and
| | - Yangchun Zhang
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; and
| | - Dongliang Xu
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; and
| | - Puyi Sheng
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; and
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44
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Abstract
There is clear evidence that patients with type 2 diabetes mellitus (T2D) have increased fracture risk, despite having high bone mineral density (BMD) and body mass index (BMI). Thus, poor bone quality has been implicated as a mechanism contributing to diabetic skeletal fragility. Poor bone quality in T2D may result from the accumulation of advanced glycation end-products (AGEs), which are post-translational modifications of collagen resulting from a spontaneous reaction between extracellular sugars and amino acid residues on collagen fibers. This review discusses what is known and what is not known regarding AGE accumulation and diabetic skeletal fragility, examining evidence from in vitro experiments to simulate a diabetic state, ex vivo studies in normal and diabetic human bone, and diabetic animal models. Key findings in the literature are that AGEs increase with age, affect bone cell behavior, and are altered with changes in bone turnover. Further, they affect bone mechanical properties and microdamage accumulation, and can be inhibited in vitro by various inhibitors and breakers (e.g. aminoguanidine, N-Phenacylthiazolium Bromide, vitamin B6). While a few studies report higher AGEs in diabetic animal models, there is little evidence of AGE accumulation in bone from diabetic patients. There are several limitations and inconsistencies in the literature that should be noted and studied in greater depth including understanding the discrepancies between glycation levels across reported studies, clarifying differences in AGEs in cortical versus cancellous bone, and improving the very limited data available regarding glycation content in diabetic animal and human bone, and its corresponding effect on bone material properties in T2D.
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Affiliation(s)
- Lamya Karim
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Department of Orthopedic Surgery, Harvard Medical School, Boston, MA 02215 USA.
| | - Mary L Bouxsein
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Department of Orthopedic Surgery, Harvard Medical School, Boston, MA 02215 USA.
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45
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Farlay D, Armas LAG, Gineyts E, Akhter MP, Recker RR, Boivin G. Nonenzymatic Glycation and Degree of Mineralization Are Higher in Bone From Fractured Patients With Type 1 Diabetes Mellitus. J Bone Miner Res 2016; 31:190-5. [PMID: 26234180 PMCID: PMC4876148 DOI: 10.1002/jbmr.2607] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 07/21/2015] [Accepted: 07/28/2015] [Indexed: 01/22/2023]
Abstract
Low-energy fractures are frequent complications in type 1 diabetes mellitus patients (T1DM). Modifications of bone intrinsic composition might be a potential cause of fragility observed in diabetic subjects. Advanced glycation end products (AGEs) were found in numerous connective tissues from T1DM patients. However, whether AGEs are present at high levels in bone matrix from diabetic subjects is unknown. Moreover, whether elevated AGEs in the bone matrix impair mineralization has not been addressed in humans. The purposes of this study were 1) to determine whether bone matrix from fracturing and nonfracturing T1DM contained more AGEs than bone from healthy patients (CTL), and 2) to compare the degree of mineralization of bone and hardness between fracturing and nonfracturing T1DM versus CTL. We analyzed iliac crest bone biopsies from 5 fracturing T1DM patients, 5 nonfracturing T1DM patients, and 5 healthy subjects, all age- and sex-matched. AGEs (pentosidine) in bone matrix was measured by high-performance liquid chromatography separately in trabecular and cortical bone. The degree of mineralization of bone (DMB) was assessed by digitized microradiography, and mechanical properties by micro- and nanohardness tests. Trabecular bone from fracturing T1DM exhibited significantly higher levels of pentosidine than CTL (p = 0.04) and was more mineralized than nonfracturing T1DM (p = 0.04) and CTL (p = 0.04). Trabecular bone was not significantly different in pentosidine between nonfracturing T1DM and CTL. Cortical bone from nonfracturing T1DM was not significantly different from CTL. Positive correlations were found between HbA1c and pentosidine (r' = 0.79, p < 0.003) and between HbA1c and DMB (r' = 0.64, p < 0.02). Both modifications could lead to less flexible bone (reduced modulus of elasticity) and a tendency toward low-energy fractures in T1DM patients.
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Affiliation(s)
- Delphine Farlay
- INSERM, UMR 1033, Lyon, France.,Université de Lyon, Lyon, France
| | - Laura A G Armas
- Osteoporosis Research Center, School of Medicine, Creighton University, Omaha, NE, USA
| | - Evelyne Gineyts
- INSERM, UMR 1033, Lyon, France.,Université de Lyon, Lyon, France
| | - Mohammed P Akhter
- Osteoporosis Research Center, School of Medicine, Creighton University, Omaha, NE, USA
| | - Robert R Recker
- Osteoporosis Research Center, School of Medicine, Creighton University, Omaha, NE, USA
| | - Georges Boivin
- INSERM, UMR 1033, Lyon, France.,Université de Lyon, Lyon, France
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46
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Yang X, Gandhi C, Rahman MM, Appleford M, Sun LW, Wang X. Age-Related Effects of Advanced Glycation End Products (Ages) in Bone Matrix on Osteoclastic Resorption. Calcif Tissue Int 2015. [PMID: 26204848 DOI: 10.1007/s00223-015-0042-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Advanced glycation end products (AGEs) accumulate in bone extracellular matrix as people age. Previous studies have shown controversial results regarding the role of in situ AGEs accumulation in osteoclastic resorption. To address this issue, this study cultured human osteoclast cells directly on human cadaveric bone slices from different age groups (young and elderly) to warrant its relevance to in vivo conditions. The cell culture was terminated on the 3rd, 7th, and 10th day, respectively, to assess temporal changes in the number of differentiated osteoclasts, the number and size of osteoclastic resorption pits, the amount of bone resorbed, as well as the amount of matrix AGEs released in the medium by resorption. In addition, the in situ concentration of matrix AGEs at each resorption pit was also estimated based on its AGEs autofluorescent intensity. The results indicated that (1) osteoclastic resorption activities were significantly correlated with the donor age, showing larger but shallower resorption pits on the elderly bone substrates than on the younger ones; (2) osteoclast resorption activities were not significantly dependent on the in situ AGEs concentration in bone matrix, and (3) a correlation was observed between osteoclast activities and the concentration of AGEs released by the resorption. These results suggest that osteoclasts tend to migrate away from initial anchoring sites on elderly bone substrate during resorption compared to younger bone substrates. However, such behavior is not directly related to the in situ concentration of AGEs in bone matrix at the resorption sites.
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Affiliation(s)
- Xiao Yang
- School of Biological Sciences and Medical Engineering, Beihang University, Beijing, China
- Department of Mechanical Engineering, The University of Texas at San Antonio (UTSA), One UTSA Circle, San Antonio, TX, 78249, USA
| | - Chintan Gandhi
- Departments of Biomedical Engineering, The University of Texas at San Antonio (UTSA), One UTSA Circle, San Antonio, TX, 78249, USA
| | - Md Mizanur Rahman
- Department of Medicine, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, USA
| | - Mark Appleford
- Departments of Biomedical Engineering, The University of Texas at San Antonio (UTSA), One UTSA Circle, San Antonio, TX, 78249, USA
| | - Lian-Wen Sun
- School of Biological Sciences and Medical Engineering, Beihang University, Beijing, China
| | - Xiaodu Wang
- Departments of Biomedical Engineering, The University of Texas at San Antonio (UTSA), One UTSA Circle, San Antonio, TX, 78249, USA.
- Department of Mechanical Engineering, The University of Texas at San Antonio (UTSA), One UTSA Circle, San Antonio, TX, 78249, USA.
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47
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Abstract
The interface between collagen and the mineral reinforcement phase, carbonated hydroxyapatite (cAp), is essential for bone's remarkable functionality as a biological composite material. The very small dimensions of the cAp phase and the disparate natures of the reinforcement and matrix are essential to the material's performance but also complicate study of this interface. This article summarizes what is known about the cAp-collagen interface in bone and begins with descriptions of the matrix and reinforcement roles in composites, of the phases bounding the interface, of growth of cAp growing within the collagen matrix, and of the effect of intra- and extrafibrilar mineral on determinations of interfacial properties. Different observed interfacial interactions with cAp (collagen, water, non-collagenous proteins) are reviewed; experimental results on interface interactions during loading are reported as are their influence on macroscopic mechanical properties; conclusions of numerical modeling of interfacial interactions are also presented. The data suggest interfacial interlocking (bending of collagen molecules around cAp nanoplatelets) and water-mediated bonding between collagen and cAp are essential to load transfer. The review concludes with descriptions of areas where new research is needed to improve understanding of how the interface functions.
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Affiliation(s)
- S R Stock
- Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Chicago, IL, 60611-3008, USA,
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48
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Pietschmann P, Mechtcheriakova D, Meshcheryakova A, Föger-Samwald U, Ellinger I. Immunology of Osteoporosis: A Mini-Review. Gerontology 2015; 62:128-37. [PMID: 26088283 DOI: 10.1159/000431091] [Citation(s) in RCA: 210] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Accepted: 05/04/2015] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis is a major cause of fractures and associated morbidity in the aged population. The pathogenesis of osteoporosis is multifactorial; whereas traditional pathophysiological concepts emphasize endocrine mechanisms, it has been recognized that also components of the immune system have a significant impact on bone. Since 2000, when the term 'osteoimmunology' was coined, novel insights into the role of inflammatory cytokines by influencing the fine-tuned balance between bone resorption and bone formation have helped to explain the occurrence of osteoporosis in conjunction with chronic inflammatory reactions. Moreover, the phenomenon of a low-grade, chronic, systemic inflammatory state associated with aging has been defined as 'inflamm-aging' by Claudio Franceschi and has been linked to age-related diseases such as osteoporosis. Given the tight anatomical and physiological coexistence of B cells and the bone-forming units in the bone marrow, a role of B cells in osteoimmunological interactions has long been suspected. Recent findings of B cells as active regulators of the RANK/RANKL/OPG axis, of altered RANKL/OPG production by B cells in HIV-associated bone loss or of a modulated expression of genes linked to B-cell biology in response to estrogen deficiency support this assumption. Furthermore, oxidative stress and the generation of advanced glycation end products have emerged as links between inflammation and bone destruction.
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Affiliation(s)
- Peter Pietschmann
- Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University Vienna, Vienna, Austria
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49
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Ohno RI, Moroishi N, Sugawa H, Maejima K, Saigusa M, Yamanaka M, Nagai M, Yoshimura M, Amakura Y, Nagai R. Mangosteen pericarp extract inhibits the formation of pentosidine and ameliorates skin elasticity. J Clin Biochem Nutr 2015; 57:27-32. [PMID: 26236097 PMCID: PMC4512896 DOI: 10.3164/jcbn.15-13] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 02/12/2015] [Indexed: 01/22/2023] Open
Abstract
The inhibition of advanced glycation end-products (AGEs) by daily meals is believed to become an effective prevention for lifestyle-related diseases. In the present study, the inhibitory effect of hot water extracts of mangosteen (Garcinia mangostana L.) pericarp (WEM) on the formation of pentosidine, one of AGEs, in vitro and in vivo and the remedial effect on skin conditions were measured. WEM significantly inhibited pentosidine formation during gelatin incubation with ribose. Several compounds purified from WEM, such as garcimangosone D and rhodanthenone B, were identified as inhibitors of pentosidine formation. Oral administration of WEM at 100 mg/day to volunteer subjects for 3 months reduced the serum pentosidine contents. Because obtaining skin biopsies from healthy volunteers is ethically difficult, AGE accumulation in the skin was estimated by a fluorescence detector. The oral administration of WEM significantly reduced the skin autofluorescence intensity, demonstrating that WEM also reduced AGE accumulation in the skin. Furthermore, the elasticity and moisture content of the skin was also improved by WEM. These results demonstrate that intakes of WEM reduces the glycation stress and results in the improvement of skin conditions.
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Affiliation(s)
- Rei-Ichi Ohno
- Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University, Kumamoto 869-1404, Japan
| | - Narumi Moroishi
- Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University, Kumamoto 869-1404, Japan
| | - Hikari Sugawa
- Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University, Kumamoto 869-1404, Japan
| | - Kazuhiro Maejima
- Food Development Laboratories, Nippon Shinyaku Co., Ltd., 14 Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan
| | - Musashi Saigusa
- Food Development Laboratories, Nippon Shinyaku Co., Ltd., 14 Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan
| | - Mikihiro Yamanaka
- Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University, Kumamoto 869-1404, Japan ; Engineering Department 2, Product Development Center, New Business Development Division, SHARP Corporation, 2613-1 Ichinomoto-cho, Tenri, Nara 632-8567, Japan
| | - Mime Nagai
- Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University, Kumamoto 869-1404, Japan
| | - Morio Yoshimura
- College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama-shi, Ehime 790-8578, Japan
| | - Yoshiaki Amakura
- College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama-shi, Ehime 790-8578, Japan
| | - Ryoji Nagai
- Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University, Kumamoto 869-1404, Japan
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50
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Ural A, Janeiro C, Karim L, Diab T, Vashishth D. Association between non-enzymatic glycation, resorption, and microdamage in human tibial cortices. Osteoporos Int 2015; 26:865-873. [PMID: 25326375 PMCID: PMC4554483 DOI: 10.1007/s00198-014-2938-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 10/08/2014] [Indexed: 12/30/2022]
Abstract
UNLABELLED To better understand the association between different components of bone quality, we investigated the relationship among in vivo generated non-enzymatic glycation, resorption, and microdamage. The results showed negative correlation between advanced glycation end-products (AGEs) and resorption independent of age highlighting the interaction between these parameters that may lead to bone fragility. INTRODUCTION Changes in the quality of bone material contribute significantly to bone fragility. In order to establish a better understanding of the interaction of the different components of bone quality and their influence on bone fragility, we investigated the relationship between non-enzymatic glycation, resorption, and microdamage generated in vivo in cortical bone using bone specimens from the same donors. METHODS Total fluorescent advanced glycation end-products (AGEs) were measured in 96 human cortical bone samples from 83 donors. Resorption pit density, average resorption pit area, and percent resorption area were quantified in samples from 48 common donors with AGE measurements. Linear microcrack density and diffuse damage were measured in 21 common donors with AGE and resorption measurements. Correlation analyses were performed between all measured variables to establish the relationships among them and their variation with age. RESULTS We found that average resorption pit area and percent resorption area decreased with increasing AGEs independently of age. Resorption pit density and percent resorption area demonstrated negative age-adjusted correlation with diffuse damage. Furthermore, average resorption pit area, resorption pit density, and percent resorption area were found to decrease significantly with age. CONCLUSIONS The current study demonstrated the in vivo interrelationship between the organic constituents, remodeling, and damage formation in cortical bone. In addition to the age-related reduction in resorption, there is a negative correlation between AGEs and resorption independent of age. This inverse relationship indicates that AGEs alter the resorption process and/or accumulate in the tissue as a result of reduced resorption and may lead to bone fragility by adversely affecting fracture resistance through altered bone matrix properties.
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Affiliation(s)
- Ani Ural
- Department of Mechanical Engineering, Villanova University, 800 Lancaster Avenue, Villanova, PA 19085, USA
| | - Colleen Janeiro
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
| | - Lamya Karim
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
| | - Tamim Diab
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
| | - Deepak Vashishth
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
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