Reprogrammed marrow adipocytes: an unexpected role in the genesis of myeloma-induced bone disease (ChIP-Seq)
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Multiple myeloma is characterized by osteolytic lesions caused by osteoclast-mediated bone resorption and reduced bone formation. A unique feature of myeloma is a failure of bone healing following successful treatment. Identification of increased adipocyte numbers in marrow of successfully treated patients led us to demonstrate that normal marrow adipocytes, when co-cultured with myeloma cells, are reprogrammed and produce adipokines that activate osteoclastogenesis and suppress osteoblastogenesis. These adipocytes have reduced expression of peroxisome proliferator-activated receptor ï§ (PPARï§) mediated by recruitment of polycomb-repressive complex 2 (PRC2) via specificity protein 1, which modifies PPARï§ promoter methylation at trimethyl lysine-27 histone H3. We confirmed the importance of PPARï§ methylation by demonstrating that adipocyte-specific knockout of EZH2, a member of the PRC2, prevents adipocyte reprogramming and reverses bone changes in vivo. These results define a heretofore unrecognized role for adipocytes in genesis of myeloma-associated bone disease and that reversal of adipocyte reprogramming has therapeutic implications.
