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      Phenomenon of osteocyte lacunar mineralization: indicator of former osteocyte death and a novel marker of impaired bone quality?

      review-article
      1 , 2 , 1
      Endocrine Connections
      Bioscientifica Ltd
      bone, osteoporosis, micropetrosis, bone fragility, bisphosphonates

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          Abstract

          An increasing number of patients worldwide suffer from bone fractures that occur after low intensity trauma. Such fragility fractures are usually associated with advanced age and osteoporosis but also with long-term immobilization, corticosteroid therapy, diabetes mellitus, and other endocrine disorders. It is important to understand the skeletal origins of increased bone fragility in these conditions for preventive and therapeutic strategies to combat one of the most common health problems of the aged population. This review summarizes current knowledge pertaining to the phenomenon of micropetrosis (osteocyte lacunar mineralization). As an indicator of former osteocyte death, micropetrosis is more common in aged bone and osteoporotic bone. Considering that the number of mineralized osteocyte lacunae per bone area can distinguish healthy, untreated osteoporotic and bisphosphonate-treated osteoporotic patients, it could be regarded as a novel structural marker of impaired bone quality. Further research is needed to clarify the mechanism of lacunar mineralization and to explore whether it could be an additional target for preventing or treating bone fragility related to aging and various endocrine diseases.

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          Most cited references92

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          Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD.

          Patients with ESRD have a high circulating calcium (Ca) x phosphate (P) product and develop extensive vascular calcification that may contribute to their high cardiovascular morbidity. However, the cellular mechanisms underlying vascular calcification in this context are poorly understood. In an in vitro model, elevated Ca or P induced human vascular smooth muscle cell (VSMC) calcification independently and synergistically, a process that was potently inhibited by serum. Calcification was initiated by release from living VSMC of membrane-bound matrix vesicles (MV) and also by apoptotic bodies from dying cells. Vesicles released by VSMC after prolonged exposure to Ca and P contained preformed basic calcium phosphate and calcified extensively. However, vesicles released in the presence of serum did not contain basic calcium phosphate, co-purified with the mineralization inhibitor fetuin-A and calcified minimally. Importantly, MV released under normal physiologic conditions did not calcify, and VSMC were also able to inhibit the spontaneous precipitation of Ca and P in solution. The potent mineralization inhibitor matrix Gla protein was found to be present in MV, and pretreatment of VSMC with warfarin markedly enhanced vesicle calcification. These data suggest that in the context of raised Ca and P, vascular calcification is a modifiable, cell-mediated process regulated by vesicle release. These vesicles contain mineralization inhibitors derived from VSMC and serum, and perturbation of the production or function of these inhibitors would lead to accelerated vascular calcification.
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            Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus.

            Collagen cross-linking, a major post-translational modification of collagen, plays important roles in the biological and biomechanical features of bone. Collagen cross-links can be divided into lysyl hydroxylase and lysyloxidase-mediated enzymatic immature divalent cross-links,mature trivalent pyridinoline and pyrrole cross-links, and glycation- or oxidation-induced non-enzymatic cross-links(advanced glycation end products) such as glucosepane and pentosidine. These types of cross-links differ in the mechanism of formation and in function. Material properties of newly synthesized collagen matrix may differ in tissue maturity and senescence from older matrix in terms of crosslink formation. Additionally, newly synthesized matrix in osteoporotic patients or diabetic patients may not necessarily be as well-made as age-matched healthy subjects. Data have accumulated that collagen cross-link formation affects not only the mineralization process but also microdamage formation. Consequently, collagen cross-linking is thought to affect the mechanical properties of bone. Furthermore,recent basic and clinical investigations of collagen cross-links seem to face a new era. For instance, serum or urine pentosidine levels are now being used to estimate future fracture risk in osteoporosis and diabetes. In this review, we describe age-related changes in collagen cross-links in bone and abnormalities of cross-links in osteoporosis and diabetes that have been reported in the literature.
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              Apoptosis regulates human vascular calcification in vitro: evidence for initiation of vascular calcification by apoptotic bodies.

              The mechanisms involved in the initiation of vascular calcification are not known, but matrix vesicles, the nucleation sites for calcium crystal formation in bone, are likely candidates, because similar structures have been found in calcified arteries. The regulation of matrix vesicle production is poorly understood but is thought to be associated with apoptotic cell death. In the present study, we investigated the role of apoptosis in vascular calcification. We report that apoptosis occurs in a human vascular calcification model in which postconfluent vascular smooth muscle cell (VSMC) cultures form nodules spontaneously and calcify after approximately 28 days. Apoptosis occurred before the onset of calcification in VSMC nodules and was detected by several methods, including nuclear morphology, the TUNEL technique, and external display of phosphatidyl serine. Inhibition of apoptosis with the caspase inhibitor ZVAD.fmk reduced calcification in nodules by approximately 40%, as measured by the cresolphthalein method and alizarin red staining. In addition, when apoptosis was stimulated in nodular cultures with anti-Fas IgM, there was a 10-fold increase in calcification. Furthermore, incubation of VSMC-derived apoptotic bodies with (45)Ca demonstrated that, like matrix vesicles, they can concentrate calcium. These observations provide evidence that apoptosis precedes VSMC calcification and that apoptotic bodies derived from VSMCs may act as nucleating structures for calcium crystal formation.

                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                April 2020
                13 March 2020
                : 9
                : 4
                : R70-R80
                Affiliations
                [1 ]Department of Osteology and Biomechanics , University Medical Center Hamburg-Eppendorf, Hamburg, Germany
                [2 ]Laboratory for Anthropology and Skeletal Biology , Institute of Anatomy, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
                Author notes
                Correspondence should be addressed to B Busse: b.busse@ 123456uke.uni-hamburg.de
                Article
                EC-19-0531
                10.1530/EC-19-0531
                7159263
                32168472
                bb540d34-f729-4d5e-bb2e-98d7193f31f8
                © 2020 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                : 24 February 2020
                : 13 March 2020
                Categories
                Review

                bone,osteoporosis,micropetrosis,bone fragility,bisphosphonates

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