The roles of bone morphogenetic proteins and their signaling in the osteogenesis of adipose-derived stem cells

Abstract

Large-size bone defects can severely compromise both aesthetics and musculoskeletal functions. Adipose-derived stem cells (ASCs)-based bone tissue engineering has recently become a promising treatment strategy for the above situation. As robust osteoinductive cytokines, bone morphogenetic proteins (BMPs) are commonly used to promote the osteogenesis of ASCs. In this process, BMP signaling plays a pivotal role. However, it remains ambiguous how the pleiotrophic BMPs are involved in the commitment of ASCs along osteogenesis instead of other lineages, such as adipogenesis. BMP receptor type-IB, extracellular signal-regulated kinase, and Wnt5a appear to be the main switches controlling the in vitro osteogenic commitment of ASCs. Tumor necrosis factor-alpha, an acute inflammatory cytokine, is reported to play an important role in mediating osteogenic commitment of ASCs in vivo. In addition, various active agents and methods have been used to enhance and accelerate the osteogenesis of ASCs through promoting BMP signaling. In this review, we summarize the current knowledge on the roles of BMPs and their signaling in the osteogenesis of ASCs in vitro and in vivo.

FIG. 1.

Schematic diagram depicting the modulation of osteogenesis of ASCs by different active agents through modulating BMP signaling pathways. ASCs, adipose-derived stem cells; BMP, bone morphogenetic protein; BMPR-II: BMP receptor type-II; ERK, extracellular signal-regulated kinase; JNK, Jun N-terminal kinase; RUNX2, Runt-related transcription factor 2; →, promotion; ⊣, inhibition. Color images available online at www.liebertpub.com/teb

FIG. 2.

Schematic diagram depicting the induction of endogeneous BMPs by different active agents for their promoting effects on the osteogenesis of ASCs. ICAT, inhibitor of β-catenin and TCF-4; Shh, sonic hedgehog; TGF-β1, transforming growth factor-β1. Color images available online at www.liebertpub.com/teb

FIG. 3.

Schematic diagram depicting the signaling pathways of BMPs in ASCs and the main switches for the osteogenic commitment of ASCs. BMPR-IA, BMP receptor type-IA; BMPR-IB, BMP receptor type-IB; BMPR-II, BMP receptor type-II; CaMK-II, calcium/calmodulin-dependent kinase II; ERK, extracellular signal-regulated kinase; LPL, lipoprotein lipase; NF-κB, nuclear factor κB; NLK, Nemo-like kinase; PPAR-γ, peroxisome proliferator-activated receptor gamma; RUNX2, Runt-related transcription factor 2; TAB2, TGF-β-activated kinase 1/MAP3K7-binding protein 2; TAK1, transforming growth factor β-activated kinase-1; TAZ, transcriptional coactivator with PDZ-binding motif; TNF-α, tumor necrosis factor-alpha. →, promotion; ⊣, inhibition. Color images available online at www.liebertpub.com/teb