The Load-Bearing Mechanosome Revisited.

We introduced the mechanosome hypothesis in 2003 as a heuristic model for investigating mechanotransduction in bone (Pavalko et al., J Cell Biochem, 2003, 88(1):104-112). This model suggested specific approaches for investigating how mechanical information is conveyed from the membrane of the sensor bone cell to the target genes and how this transmitted information from the membrane is converted into changes in transcription. The key concepts underlying the mechanosome hypothesis are that load-induced deformation of bone deforms the sensor cell membrane; embedded in the membrane are the focal adhesion and cadherin-catenin complexes, which in turn are physically connected to the chromatin via a solid-state scaffold. The physical stimulation of the membrane launches multiprotein complexes (mechanosomes) from the adhesion platforms while concomitantly tugging target genes into position for contact with the incoming mechanosomes, the carriers of the mechanical information to the nucleus. The mechanosome is comprised of an adhesion-associated protein and a nucleocytoplasmic shuttling transcription factor. Upon arrival at the target gene, mechanosomes alter DNA conformation and thus influence the interactions between trans-acting proteins along the gene, changing gene activity. Here, we update significant progress related to the mechanosome concept since publication of our original hypothesis. The launching of adhesion- and cytoskeletal-associated proteins into the nucleus toward target genes appears to be a common mechanism for regulating cell response to changes in its mechanical microenvironment.