Circulating cytokines present in multiple myeloma patients inhibit the osteoblastic differentiation of adipose stem cells.
Ladan KobariMartine AuclairOlivier PiauNathalie FerrandMaurice ZaouiFrançois DelhommeauBruno FèveMichèle SabbahLaurent GarderetPublished in: Leukemia (2021)
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.
Keyphrases
- end stage renal disease
- newly diagnosed
- mesenchymal stem cells
- stem cells
- insulin resistance
- multiple myeloma
- ejection fraction
- chronic kidney disease
- adipose tissue
- fatty acid
- peritoneal dialysis
- vascular smooth muscle cells
- rheumatoid arthritis
- bone marrow
- poor prognosis
- patient reported outcomes
- growth factor
- skeletal muscle
- transcription factor
- bone mineral density
- metabolic syndrome
- single cell
- postmenopausal women
- umbilical cord
- long non coding rna
- bone loss