BMP‐2 Signaling and Mechanotransduction Synergize to Drive Osteogenic Differentiation via YAP/TAZ

Abstract

Growth factors and mechanical cues synergistically affect cellular functions, triggering a variety of signaling pathways. The molecular levels of such cooperative interactions are not fully understood. Due to its role in osteogenesis, the growth factor bone morphogenetic protein 2 (BMP‐2) is of tremendous interest for bone regenerative medicine, osteoporosis therapeutics, and beyond. Here, contribution of BMP‐2 signaling and extracellular mechanical cues to the osteogenic commitment of C2C12 cells is investigated. It is revealed that these two distinct pathways are integrated at the transcriptional level to provide multifactorial control of cell differentiation. The activation of osteogenic genes requires the cooperation of BMP‐2 pathway‐associated Smad1/5/8 heteromeric complexes and mechanosensitive YAP/TAZ translocation. It is further demonstrated that the Smad complexes remain bound onto and active on target genes, even after BMP‐2 removal, suggesting that they act as a “molecular memory unit.” Thus, synergistic stimulation with BMP‐2 and mechanical cues drives osteogenic differentiation in a programmable fashion.

BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF

“…In accordance, ID1, a Hippo target protein, was earlier suggested to be upregulated by BMP6 in microvascular cells [ 68 ]. TAZ/YAP was also demonstrated to regulate BMP4 expression in zebrafish [ 69 ], and indirectly crosstalk with BMP2 signaling pathway [ 70 ]. Additionally, BMP2 has been suggested to induce cytoplasmic retention of YAP [ 71 ].…”

Ligand Diffusion Enables Force‐Independent Cell Adhesion via Activating α5β1 Integrin and Initiating Rac and RhoA Signaling

“…The mechanical properties of the materials to which cells adhere play a major role in regulating cellular mechanotransduction. [ 1 ] While the mechanisms governing cellular mechanotransduction on materials with static properties, e.g., stiffness, [ 2–4 ] geometry, [ 5 ] topography, [ 6,7 ] or spatial ligand patterning [ 8,9 ] are increasingly characterized, less is known about mechanosensitive cellular response to materials with dynamic properties. In general, actomyosin contractility in response to mechanical stimulation causes enhanced cytoskeletal filament assembly and focal adhesion formation, which in turn result in unfolding of structural “molecular strain gauge” proteins and subsequent activation of mechanosensitive signaling pathways.…”

Differential bioactivity of four BMP-family members as function of biomaterial stiffness

“…Mechanotransduction via the ECM is known to involve the adhesion receptors integrins and to be sensitive to matrix stiffness 19,20 . Indeed, BMP signaling can be modulated by integrins 21 , matrix stiffness and cytoskeletal tension 22 .…”