Adipocytes have traditionally been seen as fat storage cells, but studies from the past decade have highlighted a role for adipocytes in tumour growth. Now, a new paper published in Science Translational Medicine reports that these multifaceted cells also have a function in tumour-associated bone disease. Specifically, the authors show that following exposure to myeloma cells, adipocytes are reprogrammed and gain the ability to resorb bone.

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“Our lab is interested in the pathogenesis of myeloma-associated bone disease, with a specific focus on how myeloma cells regulate bone remodelling,” explains corresponding author Jing Yang. “While observing the bone marrow specimens from patients in remission, we could not overlook the prominent presence of adipocytes around the bone.” This observation led the authors to hypothesize that adipocytes might have a critical role in the bone lesions themselves.

To investigate their hypothesis, the authors first recreated the adipocyte–bone phenomenon seen in patients in remission in a humanized mouse model. The mouse model reflects the different stages of disease whereby it first displays an active myeloma, then after treatment, the model stays in remission. The team found that mice that were injected with conditioned medium from adipocytes obtained from patients with newly diagnosed myeloma caused multiple large lytic lesions. By contrast, mice that were injected with control medium were found to have little bone resorption.

Next, Yang and colleagues created adipocyte-specific enhancer of zeste homologue 2 (EZH2)-knockout mice to evaluate the importance of EZH2 enzymatic activity in the failure of bone healing. To model myeloma in remission, the investigators injected murine myeloma into EZH2-knockout mice before treating them with chemotherapy. The team then evaluated the extent to which the myeloma was resolved by assessing levels of M-protein, which is an indicator of myeloma burden, and CD138+ myeloma cell infiltration in marrow or other organs. Following an assessment of the mice 2 weeks after treatment, Yang and colleagues could only detect a few infiltrated CD138+ cells and could not detect any M-protein, suggesting that the mice were almost free of myeloma.

“Our study provides an explanation for the mechanism of lytic bone disease development in patients with active myeloma, but questions regarding why bone lesions persist in patients after treatment — even when in remission — still remain,” concludes Yang. “We are now planning to investigate how other stromal cells are involved in the failure of bone healing in patients in remission so as to get a complete picture within marrow niche.”