Roles of MicroRNAs in Osteogenesis or Adipogenesis Differentiation of Bone Marrow Stromal Progenitor Cells

Abstract

Bone marrow stromal cells (BMSCs) are multipotent cells which can differentiate into chondrocytes, osteoblasts, and fat cells. Under pathological stress, reduced bone formation in favour of fat formation in the bone marrow has been observed through a switch in the differentiation of BMSCs. The bone/fat switch causes bone growth defects and disordered bone metabolism in bone marrow, for which the mechanisms remain unclear, and treatments are lacking. Studies suggest that small non-coding RNAs (microRNAs) could participate in regulating BMSC differentiation by disrupting the post-transcription of target genes, leading to bone/fat formation changes. This review presents an emerging concept of microRNA regulation in the bone/fat formation switch in bone marrow, the evidence for which is assembled mainly from in vivo and in vitro human or animal models. Characterization of changes to microRNAs reveals novel networks that mediate signalling and factors in regulating bone/fat switch and homeostasis. Recent advances in our understanding of microRNAs in their control in BMSC differentiation have provided valuable insights into underlying mechanisms and may have significant potential in development of new therapeutics.

Keywords: BMSC differentiation; bone/fat formation; microRNAs.

Figure 1

Wnt/β-catenin signalling involved in bone or fat regulation. (Left) In case Wnt ligand is binding to co-receptor complex, β-catenin is released from the destruction complex composed of GSK-3β, Axin and APC. This allows β-catenin to be accumulated and translocated into nucleus. By interacting with TCF/LEF transcription factors, β-catenin activates the osteogenic-related gene transcription program and promotes osteogenesis and bone formation. (Right) In case Wnt ligand is not able to bind to its co-receptor complex (e.g., in the presence of Wnt antagonists (sFRP-1, WIF-1, DKKs and sclerostin)), β-catenin is sequestered by the degradation complex, phosphorylated and subsequently degraded. Attenuated β-catenin enhances adipogenesis and marrow fat formation. Wnt: Wingless; LRP5/6: low-density lipoprotein receptor-related protein 5/6; Frizzled: FZD; DVL: disheveled; GSK-3β: glycogen synthase kinase 3β; APC: adenomatous polyposis coli; TCF/LEF: T-cell factor/lymphoid enhancer-binding factor; RUNX2: runt-related transcription factor 2; DLX5: distal-less homeobox 5; OSX: osterix; PPARγ: peroxisome proliferator-activated receptor γ; C/EBPα: CCAAT/enhancer-binding protein α.

Figure 2

TGF-β/BMP signalling involved in bone or fat regulation. Active TGF-β or BMP binds to TGF-βR I/II or BMPR I/II receptor complex and can induce Smad-dependent signalling. R-Smads (Smad2/3 for TGF-β signalling and Smad1/5/8 for BMPs signalling) complexes with C-Smad, Smad4 and together translocate into the nucleus, where they regulate target gene expression. Smad7 with SMURF 1/2 negatively regulates Smad-dependent signalling by preventing Smad2/3 phosphorylation. Also, Smad6 inhibits the R-Smads/Smad4 complex to disrupt BMP signalling. TGF-β/Smad signalling promotes early differentiation of osteoprogenitors while it represses osteoblast maturation, mineralization, and transition into osteocyte. BMP-Smad signalling promotes almost each step during osteoblast differentiation and induces PPARγ expression for adipogenesis. However, TGF-β/Smad signalling negatively regulates adipogenesis and marrow fat formation. TGF-β: transforming growth factor β; BMPs: bone morphogenetic proteins; TGF-βR: TGF-β receptor; BMPR: BMP receptor; R-Smads; receptor-Smads; C-Smads: common-Smads; I-Smads: inhibitory-Smads; SMURF 1/2: Smad ubiquitin regulatory factor 1 and 2.

Figure 3

MicroRNA biogenesis. MicroRNAs are transcribed in the nucleus as pri-microRNAs. Pri-microRNAs are trimmed by Draosha-DGCR8 RNase complex and proceeded into pre-microRNAs that can be exported to the cytoplasm depending on the exportin 5/GTP61 translocation system. The Dicer complex binds to pre-microRNAs, which can be cleaved into microRNA duplexes containing guide and passenger strands. The guide strand often combines with AGO2 and GW182 as microRNA-inducing slicing complex and then interacts with the target mRNA, leading to target translation suppression or degradation. AGO2: argonaute 2; TRBP: transactivation response element RNA-binding protein.

Figure 4

Roles of microRNAs in osteogenesis and adipogenesis. The list of reported microRNAs operates the network of key signalling pathways and factors to regulate bone and marrow fat formation. Green arrows mean positive effects and red arrow represent negative effects.