Contribution of Osteocytes to the Musculoskeletal Effects of Multiple Myeloma

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Contribution of Osteocytes to the Musculoskeletal Effects of Multiple Myeloma MPI: Roodman and Bellido 7. Abstract Osteolytic cancer in bone (OCIB) occurs frequently in cancer patients and is a major contributor to decreased survival and quality of life. Pathologic fractures caused by OCIB in multiple myeloma (MM) increases their risk of death >20% compared to patients without fractures. In addition, OCIB induced severe systemic muscle dysfunction further negatively impacting the performance status, quality of life, and survival. Although much is known about the contribution of tumor cells, osteoclasts, osteoblasts, stroma cells, and immune cells to the bone destructive process in OCIB, the role of osteocytes (Ots), the most numerous cell type in the skeleton and major regulators of bone remodeling, is unknown. Studies leading to this application showed that, although Ots reside deep in mineralized matrix, they are major contributors to the effects of OCIB. MM cells and Ots physically interact in vivo, and these interactions activate bidirectional Notch signaling driving MM cell proliferation and Ot apoptosis, and enhance the osteoclastogenic potential of Ots. MM-Ot interactions increase RANKL, TNFα, cyclinD1 and Notch1-4 receptor expression in MM cells, and upregulate RANKL and the inhibitor of bone formation, sclerostin, in Ots. Our studies also suggest that MIP-1 and HMGB1, known stimulators of RANKL, may also be involved because MM-derived MIP-1 acts directly to increase acid- induced HMGB1 by Ots. Further, RANKL, MIP-1 and HMGB1-driven bone resorption could also induce muscle dysfunction in MM. This proposal will test the hypothesis that MM-Ot interactions are major contributors to OCIB through increasing tumor growth and bone resorption, decreasing bone formation, and inducing muscle dysfunction. This hypothesis will be advanced by pursuing specific aims that combine in vitro, ex vivo and in vivo approaches, using osteocytic cell lines, authentic osteocytes, human and murine MM cells lines, primary MM cells derived from patients, bones from genetically modified mice, and a mouse model of MM. Aim 1 will determine the impact of bidirectional MM/Ot Notch signaling on OCIB using genetic and pharmacological tools that interfere with Notch activation. Aim 2 will determine the contribution of MM- and Ot-derived RANKL to OCIB and the role of HMGB1 and MIP-1 in RANKL regulation. And Aim 3 will determine the role of sclerostin induced by MM/Ot interactions in tumor burden, bone disease, and muscle dysfunction induced by OCIB.