BMP signalling in a mechanical context - Implications for bone biology

Bone Morphogenetic Proteins (BMPs) are extracellular multifunctional signalling cytokines and members of the TGFβ super family. These pleiotropic growth factors crucially promote bone formation, remodeling and healing after injury. Additionally, bone homeostasis is systematically regulated by mechanical inputs from the environment, which are incorporated into the bone cells' biochemical response. These inputs range from compression and tension induced by the movement of neighboring muscle, to fluid shear stress induced by interstitial fluid flow in the canaliculi and in the vascular system. Although BMPs are widely applied in a clinic context to promote fracture healing, it is still elusive how mechanical inputs modulate this signalling pathway, hindering an efficient and side-effect free application of these ligands in bone healing. This review aims to summarize the current understanding in how mechanical cues (tension, compression, shear force and hydrostatic pressure) and substrate stiffness modulate BMP signalling. We highlight the time-dependent effects in modulating immediate early up to long-term effects of mechano-BMP crosstalk during bone formation and remodeling, considering the interplay with other already established mechanosensitive pathways, such as MRTF/SRF and Hippo signalling.