Mechanical regulation of skeletal development.

Development of the various components of a normal skeleton requires highly regulated signalling systems that co-ordinate spatial and temporal patterns of cell division, cell differentiation, and morphogenesis. Much work in recent decades has revealed cascades of molecular signalling, acting through key transcription factors to regulate, for example, organized chondrogenic and osteogenic differentiation. It is now clear that mechanical stimuli are also required for aspects of skeletogenesis but very little is known about how the mechanical signals are integrated with classic biochemical signalling. Spatially organized differentiation is vital to the production of functionally appropriate tissues contributing to precise, region specific morphologies, for example transient chondrogenesis of long bone skeletal rudiments, which prefigures osteogenic replacement of the cartilage template, compared with the production of permanent cartilage at the sites of articulation. Currently a lack of understanding of how these tissues are differentially regulated hampers efforts to specifically regenerate stable bone and cartilage. Here, we review current research revealing the influence of mechanical stimuli on specific aspects of skeletal development and refer to other developing systems to set the scene for current and future work to uncover the molecular mechanisms involved. We integrate this with a brief overview of the effects of mechanical stimulation on stem cells in culture bringing together developmental and tissue engineering aspects of mechanoregulation of cell behavior. A better understanding of the molecular mechanisms that link mechanical stimuli to transcriptional control guiding cell differentiation will lead to new ideas about how to effectively prime stem cells for tissue engineering and regenerative therapies.