Bone degenerative diseases such as osteoporosis, periodontitis, and rheumatoid arthritis are major health care concerns for the elderly population that is rapidly increasing in the US. An osteoporotic fracture can cause significant morbidity and mortality. Tooth loss due to periodontitis causes problems in mastication, pronunciation, and esthetics. Rheumatoid arthritis induces joint damage and eventual disability. Consequently, bone degenerative diseases cause significant impairment in quality of life for many Americans and the impact on public health is enormous. In such diseases, osteoclast activity typically predominates over osteoblast activity. Hence, suppression of osteoclasts is a therapeutic strategy for the prevention and treatment of degenerative bone diseases. We have found, in preliminary studies, that homozygous mutant mice for B-cell leukemia/lymphoma 2 (Bcl2-/-) have altered hematopoietic components and high bone mass with suppressed osteoclast numbers, and that Bcl2-/- osteoclastogenesis in bone marrow mononuclear cell cultures is significantly more robust than wild-type osteoclastogenesis but vanishes quickly. Endogenous receptor activator for nuclear factor-kappa B ligand (RANKL) levels are comparable between Bcl2+/+ and Bcl2-/- in these cultures. Osteoblast activity is not affected in vivo or ex vivo. Bcl2-/- osteoblasts are normal in their cellular activity, such as proliferation, differentiation, mineral formation, and staurosporine-induced apoptosis. Interestingly, when osteoclastogenesis is induced in bone marrow-derived monocytic cell cultures, Bcl2-/- osteoclastogenesis is no longer robust and short-lived and there are no differences in the course of osteoclastogenesis between Bcl2+/+ and Bcl2-/-. These data suggest that Bcl2 plays a role essentially in osteoclast progenitor populations. Therefore, Bcl2 signaling in osteoclast progenitors could be a therapeutic target for bone diseases where osteoclast activity is predominant. In this project, the hypothesis that Bcl2 regulates osteoclastogenesis by modulating differentiation of CD11b- cells to CD11b+ osteoclast progenitors will be tested.
In Aim 1, the impact of Bcl2 on osteoclast progenitor populations will be assessed.
In Aim 2, the role of Bcl2 in the regulation of calcineurin-nuclear factor of activated T-cell (NFAT) signaling in the progenitors (CD11b- cells) and its impact on osteoclastogenesis and their survival will be investigated. Findings from these Specific Aims will provide mechanistic insight into the finding that Bcl2-/- mice have altered hematopoietic components with suppressed osteoclasts in vivo, and will contribute to establish a strategy to suppress osteoclastogenesis by modulating progenitor cells. This study is critical to clarify the role of Bcl2 in osteoclast progenitors and osteoclastogenesis. Public Health Relevance: Enhanced osteoclast activity accelerates disease progression of osteoporosis, periodontitis, and rheumatoid arthritis. Bcl2 could be a therapeutic target to suppress osteoclasts. This project will clarify the Bcl2 regulation of osteoclastogenesis via osteoclast progenitors.
Enhanced osteoclast activity accelerates disease progression of osteoporosis, periodontitis, and rheumatoid arthritis. Bcl2 could be a therapeutic target to suppress osteoclasts. This project will clarify the Bcl2 regulation of osteoclastogenesis via osteoclast progenitors.
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