Reprogrammed marrow adipocytes: an unexpected role in the genesis of myeloma-induced bone disease

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 γ (PPARγ) mediated by recruitment of polycomb-repressive complex 2 (PRC2) via specificity protein 1, which modifies PPARγ promoter methylation at trimethyl lysine-27 histone H3. We confirmed the importance of PPARγ 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. Normal adipocytes (nADs) isolated from normal bone marrow samples (n = 6) and the marrow of myeloma patients in complete remission (CR Pt; n = 12), Then total RNA was extracted and used for comparison by gene expression profiling.