Mechanobiology of TGFß signaling in the skeleton.

Physical and biochemical cues play fundamental roles in the skeleton at both the tissue and cellular levels. The precise coordination of these cues is essential for skeletal development and homeostasis, and disruption of this coordination can drive disease progression. The growth factor TGFß is involved in both the regulation of and cellular response to the physical microenvironment. It is essential to summarize the current findings regarding the mechanisms by which skeletal cells integrate physical and biochemical cues so that we can identify and address remaining gaps that could ultimately improve skeletal health. In this review, we describe the role of TGFß in mechanobiological signaling in bone and cartilage at the tissue and cellular levels. We provide detail on how static and dynamic physical cues at the macro-level are transmitted to the micro-level, ultimately leading to regulation at each level of the TGFß pathway and to cell differentiation. The continued integration of engineering and biological approaches is needed to answer many remaining questions, such as the mechanisms by which cells generate a coordinated response to physical and biochemical cues. We propose one such mechanism, through which the combination of TGFß and an optimal physical microenvironment leads to synergistic induction of downstream TGFß signaling.

Discrete spatial organization of TGFß receptors couples receptor multimerization and signaling to cellular tension.

Cell surface receptors are central to the cell's ability to generate coordinated responses to the multitude of biochemical and physical cues in the microenvironment. However, the mechanisms by which receptors enable this concerted cellular response remain unclear. To investigate the effect of cellular tension on cell surface receptors, we combined novel high-resolution imaging and single particle tracking with established biochemical assays to examine TGFß signaling. We find that TGFß receptors are discretely organized to segregated spatial domains at the cell surface. Integrin-rich focal adhesions organize TßRII around TßRI, limiting the integration of TßRII while sequestering TßRI at these sites. Disruption of cellular tension leads to a collapse of this spatial organization and drives formation of heteromeric TßRI/TßRII complexes and Smad activation. This work details a novel mechanism by which cellular tension regulates TGFß receptor organization, multimerization, and function, providing new insight into the mechanisms that integrate biochemical and physical cues.