Sorbonne Université-INSERM, UMR_S938, Centre de Recherche Saint-Antoine-Team Hematopoietic and Leukemic Development, Institut Universitaire de Cancérologie, Paris, 75012, France.
Sorbonne Université-INSERM, UMR_S938, Centre de Recherche Saint-Antoine-Team Lipodystrophies, Metabolic and Hormonal Adaptations, and Aging, Institut Hospitalo-Universitaire de Cardiométabolisme et Nutrition (ICAN), Paris, 75012, France.
Leukemia. 2022 Feb;36(2):540-548. doi: 10.1038/s41375-021-01428-6. Epub 2021 Sep 23.
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.
骨髓瘤的特征是骨病变，这与破骨细胞活性增加以及骨髓间充质干细胞（MSCs）向成骨细胞分化缺陷有关。在骨髓环境之外，脂肪细胞衍生的 MSCs（ASCs）可能代表功能性成骨细胞的来源。然而，我们最近发现骨髓瘤患者（MM-ASCs）的 ASC 成骨分化存在缺陷。我们研究了骨髓瘤患者初诊时（MM-血浆）和完全缓解时（CR-血浆）以及健康供体的血浆对健康供体来源的 ASC（HD-ASC）的成骨分化的影响。HD-ASC 的成骨发生被 MM-血浆抑制。七种细胞因子（ANG1、ENA-78、EGF、PDGF-AA/AB/BB 和 TARC）在 MM-血浆中增加，并分别抑制 HD-ASC 的成骨分化。通过 RNA 测序比较 MM-ASCs 和 HD-ASCs 显示，与 HD-ASCs 相比，两个表征脂肪细胞分化的主基因 CD36 和 PPARγ 在 MM-ASCs 中上调。最后，我们证明在 MM-血浆或七种细胞因子单独存在的情况下，HD-ASCs 中 CD36 和 PPARγ 的表达显著增加，与 MM-ASCs 相似。我们得出结论，MM 血浆中的特定细胞因子，除了众所周知的 DKK1 外，还会抑制 MM-和 HD-ASCs 的成骨分化，并偏向脂肪细胞分化。
