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      Positive and negative regulators of osteoclast apoptosis

      review-article
      a , * , b
      Bone Reports
      Elsevier
      Osteoclasts, Apoptosis, FAS/FASL system, TRAIL/TRAILR system, Estrogen

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          Abstract

          Survival and apoptosis are of major importance in the osteoclast life cycle. As osteoclasts have short lifespan, any alteration that prolongs their viability may cause enhanced osteoclast activity. Hence, the regulation of OC apoptosis has been recognized as a critical factor in bone remodeling. An imbalance in bone remodeling due to increased osteoclast activity leads to most adult bone diseases such as osteoporosis, rheumatoid arthritis and multiple myeloma. Therefore, manipulating osteoclast death would be a viable therapeutic approach in ameliorating bone diseases, with accelerated resorption. Over the last few decades we have witnessed the unraveling of many of the intracellular mechanisms responsible for osteoclast apoptosis. Thus, an understanding of the underlying mechanisms by which osteoclasts undergo programmed cell death and the regulators that modulate that activity will undoubtedly provide an insight into the development of pharmacological agents to treat such pathological bone diseases.

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          Most cited references99

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          Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis.

          The adult skeleton regenerates by temporary cellular structures that comprise teams of juxtaposed osteoclasts and osteoblasts and replace periodically old bone with new. A considerable body of evidence accumulated during the last decade has shown that the rate of genesis of these two highly specialized cell types, as well as the prevalence of their apoptosis, is essential for the maintenance of bone homeostasis; and that common metabolic bone disorders such as osteoporosis result largely from a derangement in the birth or death of these cells. The purpose of this article is 3-fold: 1) to review the role and the molecular mechanism of action of regulatory molecules, such as cytokines and hormones, in osteoclast and osteoblast birth and apoptosis; 2) to review the evidence for the contribution of changes in bone cell birth or death to the pathogenesis of the most common forms of osteoporosis; and 3) to highlight the implications of bone cell birth and death for a better understanding of the mechanism of action and efficacy of present and future pharmacotherapeutic agents for osteoporosis.
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            Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts.

            Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor alpha (ERalpha) in mediating estrogen-dependent bone maintenance in female mice. We selectively ablated ERalpha in differentiated osteoclasts (ERalpha(DeltaOc/DeltaOc)) and found that ERalpha(DeltaOc/DeltaOc) females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, we show that estrogen induced apoptosis and upregulation of Fas ligand (FasL) expression in osteoclasts of the trabecular bones of WT but not ERalpha(DeltaOc/DeltaOc) mice. The expression of ERalpha was also required for the induction of apoptosis by tamoxifen and estrogen in cultured osteoclasts. Our results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogen as well as SERMs.
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              Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice.

              To understand the normal, physiological role of the c-src proto-oncogene, a null mutation was introduced into the gene by homologous recombination in mouse embryonic stem cells. Two independent targeted clones were used to generate chimeras that transmitted the mutated allele to their offspring. Intercrossing of heterozygotes gave rise to live born homozygotes, but most of these mice died within the first few weeks of birth. Histological and hematological examination of the homozygous mutants did not reveal detectable abnormalities in the brain or platelets, where src is most highly expressed. However, these mutants were deficient in bone remodeling, indicating impaired osteoclast function, and developed osteopetrosis. These results demonstrate that src is not required for general cell viability (possibly because of functional overlap with other tyrosine kinases related to src) and uncover an essential role for src in bone formation.
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                Author and article information

                Contributors
                Journal
                Bone Rep
                Bone Rep
                Bone Reports
                Elsevier
                2352-1872
                21 October 2019
                December 2019
                21 October 2019
                : 11
                : 100225
                Affiliations
                [a ]Division of Pharmacology, Department of Oral Medicine and Periodontology, Faculty of Dental Sciences, University of Peradeniya, Sri Lanka
                [b ]Department of Biochemistry, Faculty of Medicine, University of Peradeniya, Sri Lanka
                Author notes
                [* ]Corresponding author. niroshanis@ 123456pdn.ac.lk
                Article
                S2352-1872(19)30031-2 100225
                10.1016/j.bonr.2019.100225
                6838739
                31720316
                ab9954f8-f592-467c-8fec-d35fe03f25e0
                © 2019 Published by Elsevier Inc.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 19 March 2019
                : 22 August 2019
                : 2 October 2019
                Categories
                Article

                osteoclasts,apoptosis,fas/fasl system,trail/trailr system,estrogen

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