Upregulation of miR-135b is involved in the impaired osteogenic differentiation of mesenchymal stem cells derived from multiple myeloma patients.
Previous studies have demonstrated that mesenchymal stem cells from multiple myeloma (MM) patients (MM-hMSCs) display a distinctive gene expression profile, an enhanced production of cytokines and an impaired osteogenic differentiation ability compared to normal donors (ND-hMSCs). However, the underlying molecular mechanisms are unclear. In the present study, we observed that MM-hMSCs exhibited an abnormal upregulation of miR-135b, showing meanwhile an impaired osteogenic differentiation and a decrease of SMAD5 expression, which is the target of miR-135b involved in osteogenesis. By gain and loss of function studies we confirmed that miR-135b negatively regulated hMSCs osteogenesis. We also found that MM cell-produced factors stimulated ND-hMSCs to upregulate the expression of miR-135b. Importantly, treatment with a miR-135b inhibitor promoted osteogenic differentiation in MM-hMSCs. Finally, we observed that MM cell-derived soluble factors could induce an upregulation of miR-135b expression in ND-hMSCs in an indirect coculture system and the miR-135b expression turned to normal level after the removal of MM cells. Collectively, we provide evidence that miR-135b is involved in the impaired osteogenic differentiation of MSCs derived from MM patients and might therefore be a promising target for controlling bone disease.
Department of Lung Cancer Surgery, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, P.R.China ; Stem Cell Laboratory-Division Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium ; Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels, Brussels, Belgium.
Song
S
Xu
Gaia
G
Cecilia Santini
Kim
K
De Veirman
Isabelle
I
Vande Broek
Xavier
X
Leleu
Ann
A
De Becker
Ben
B
Van Camp
Karin
K
Vanderkerken
Ivan
I
Van Riet
D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation; D005260:Female; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000473:pathology*; D010012:Osteogenesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics; D015854:Up-Regulation
C544965:MIRN135 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D051902:Smad5 Protein