Mechanoreception at the cellular level: the detection, interpretation, and diversity of responses to mechanical signals

Abstract

Cells from diverse tissues detect mechanical load signals by similar mechanisms but respond differently. The diversity of responses reflects the genotype of the cell and the mechanical demands of the resident tissue. We hypothesize that cells maintain a basal equilibrium stress state that is a function of the number and quality of focal adhesions, the polymerization state of the cytoskeleton, and the amount of extrinsic, applied mechanical deformation. A load stimulus detected by a mechano-electrochemical sensory system, including mechanically sensitive ion channels, integrin-cytoskeleton machinery, and (or) a load-conformation sensitive receptor or nonreceptor tyrosine kinase, may activate G proteins, induce second messengers, and activate an RPTK or JAK/STAT kinase cascade to elicit a response. We propose the terms autobaric to describe a self-loading process, whereby a cell increases its stress state by contracting and applying a mechanical load to itself, and parabaric, whereby a cell applies a load to an adjacent cell by direct contact or through the matrix. We predict that the setpoint for maintaining this basal stress state is affected by continuity of incoming mechanical signals as deformations that activate signalling pathways. A displacement of the cytoskeletal machinery may result in a conformational change in a kinase that results in autophosphorylation and cascade initiation. pp60Src is such a kinase and is part of a mechanosensory protein complex linking integrins with the cytoskeleton. Cyclic mechanical load induces rapid Src phosphorylation. Regulation of the extent of kinase activation in the pathway(s) may be controlled by modulators such as G proteins, kinase phosphorylation and activation, and kinase inhibitors or phosphatases. Intervention at the point of ras-raf interaction may be particularly important as a restriction point.

Tenocyte responses to mechanical loading in vivo: A role for local insulin‐like growth factor 1 signaling in early tendinosis in rats

“…In cultured human osteoblasts, ERK-1/2 blockade prevented shear-induced proliferation and matrix synthesis (43). Tenocytes appear to share elements of a load-sensing mechanism similar to osteoblasts and osteocytes; stretch-activated potassium and calcium channels, internal calcium release, interstitial ATP release, and gap junction signaling all play a role in the proliferative response to membrane deformation, substrate deformation, or fluid shear (43)(44)(45)(46)(47). In elongated tenocytes, proliferation and collagen synthesis in response to ex vivo loading of chicken flexor tendon could be blocked by a gap junction inhibitor (48).…”

Periodontal ligament cells under intermittent tensile stress regulate mRNA expression of osteoprotegerin and tissue inhibitor of matrix metalloprotease-1 and -2

“…Several studies have reported that mechanical stimuli regulate various cellular functions and that the mechano-sensing system including ion channel receptors, soluble cytokines, the cytoskeleton or intracellular signaling pathways are likely to be involved in the signaling of and response to mechanical stresses in mammalian cells [2][3][4]. The regulatory role of mechanical force is believed to be critical in the remodeling of the skeleton.…”

Cyclic tensile stretch inhibition of nitric oxide release from osteoblast‐like cells is both G protein and actin‐dependent

“…This mechanotransduction in bone must include the biochemical coupling which transduces a local mechanical signal into a biochemical signal [2]. Recent observations suggest the presence of a mechanotransducer that resides in the cell membrane of the osteoblastlike cells [15].…”