The Load-Bearing Mechanosome Revisited

Abstract

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.

Src mediates the mechanical activation of myogenesis by activating TNFα-converting enzyme

“…The mechanosome concept, developed in studies of bone cells, indicates that Src is a key component of mechanosomes, which convert mechanical stress into biochemical signals (Bidwell and Pavalko, 2010;Rangaswami et al, 2010). Our observation that in mechanically stimulated MPCs, activated Src colocalizes with activated TACE in clusters suggests that TACE is a component of mechanosomes.…”

Mechanotransduction in the Endothelium: Role of Membrane Proteins and Reactive Oxygen Species in Sensing, Transduction, and Transmission of the Signal with Altered Blood Flow

“…Under constant laminar flow, the mechanosome network is essentially inactive (OFF mechanosome); alteration of shear forces (ON mechanosome) results in sensing of shear. The concept of the mechanosome has been applied previously to bone loading (13,14,111), but here the concept is broadened to include the vascular endothelium and possibly other cell types.…”

“…The mechanosome can be defined as a network of mechanosensors and transducers that transmit a physical force into a biochemical and transcriptional activity that alters cellular structure and function. This term has been applied previously in studies of bone (13,14,111). We posit that the mechanosome on the EC membrane consists of caveolae, PECAM, VEGFR, VE-cadherin and possibly other elements (Fig.…”

Mechanical regulation of signaling pathways in bone

“…The increase in unbound β-catenin coupled with activation of GSK3β and Akt that occurs after fluid shear stress has been proposed as a potential upstream regulator of β-catenin nuclear translocation. Thus, cadherins may serve as launching platforms for β-catenin in response to mechanical stimulation (Bidwell and Pavalko, 2010). …”