Myeloma is characterized by bone lesions, which are related to both an increased osteoclast activity and a defect in the differentiation of medullary mesenchymal stem cells (MSCs) into osteoblasts. Outside the medullary environment, adipocyte-derived MSCs (ASCs) could represent a source of functional osteoblasts. However, we recently found a defect in the osteoblastic differentiation of ASCs from myeloma patients (MM-ASCs). We examined the effects of plasma from myeloma patients at diagnosis (MM-plasmas) and in complete remission (CR-plasmas) and from healthy donors on the osteoblastic differentiation of healthy donor-derived ASCs (HD-ASCs). Osteoblastogenesis in HD-ASCs was suppressed by MM-plasmas. Seven cytokines (ANG1, ENA-78, EGF, PDGF-AA/AB/BB, and TARC) were increased in MM-plasmas and separately inhibited the osteoblastic differentiation of HD-ASCs. Comparison of MM-ASCs and HD-ASCs by RNA sequencing showed that two master genes characterizing adipocyte differentiation, CD36 and PPARγ, were upregulated in MM-ASCs as compared to HD-ASCs. Finally, we demonstrated a significant increase in CD36 and PPARγ expression in HD-ASCs in the presence of MM-plasmas or the seven cytokines individually, similarly as in MM-ASCs. We conclude that specific cytokines in MM-plasmas, besides the well-known DKK1, inhibit the osteoblastic differentiation of MM- and HD-ASCs with a skewing towards adipocyte differentiation.
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This study was financially supported by the Institut National de Santé et de Recherche Médicale (INSERM), the Sorbonne University, the Centre de Recherche Saint-Antoine, the Groupement d’Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Intergroupe Francophone du Myélome (IFM) and the Fondation pour la Recherche Médicale (BF, FRM EQU2019 030077868). This work benefited from equipment and services from the iGenSeq (RNA sequencing) and iCONICS (RNAsequence analyses) core facilities of the ICM (Institut du Cerveau et de la Moelle épinière, Hôpital Pitié Salpêtrière, Paris, France). The authors acknowledge the valuable assistance of Romain Morichon of the Sorbonne Université-INSERM, UMR_S938, Centre de Recherche Saint-Antoine Imagery platform.
The authors declare no competing interests.
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Kobari, L., Auclair, M., Piau, O. et al. Circulating cytokines present in multiple myeloma patients inhibit the osteoblastic differentiation of adipose stem cells. Leukemia (2021). https://doi.org/10.1038/s41375-021-01428-6