Molecular pathways mediating mechanical signaling in bone

Abstract

Bone tissue has the capacity to adapt to its functional environment such that its morphology is "optimized" for the mechanical demand. The adaptive nature of the skeleton poses an interesting set of biological questions (e.g., how does bone sense mechanical signals, what cells are the sensing system, what are the mechanical signals that drive the system, what receptors are responsible for transducing the mechanical signal, what are the molecular responses to the mechanical stimuli). Studies of the characteristics of the mechanical environment at the cellular level, the forces that bone cells recognize, and the integrated cellular responses are providing new information at an accelerating speed. This review first considers the mechanical factors that are generated by loading in the skeleton, including strain, stress and pressure. Mechanosensitive cells placed to recognize these forces in the skeleton, osteoblasts, osteoclasts, osteocytes and cells of the vasculature are reviewed. The identity of the mechanoreceptor(s) is approached, with consideration of ion channels, integrins, connexins, the lipid membrane including caveolar and non-caveolar lipid rafts and the possibility that altering cell shape at the membrane or cytoskeleton alters integral signaling protein associations. The distal intracellular signaling systems on-line after the mechanoreceptor is activated are reviewed, including those emanating from G-proteins (e.g., intracellular calcium shifts), MAPKs, and nitric oxide. The ability to harness mechanical signals to improve bone health through devices and exercise is broached. Increased appreciation of the importance of the mechanical environment in regulating and determining the structural efficacy of the skeleton makes this an exciting time for further exploration of this area.

Fig. 1

Mechanical force in the cellular environment. Skeletal loading generates deformation of the hard tissue with strain across the cell's substrate, pressure in the intramedullary cavity and within the cortices with transient pressure waves, shear forces through cannaliculi which cause drag over cells, and dynamic electric fields as interstitial fluid flows past charged bone crystals.

Fig. 2

Mechanosensors activate intracellular signals. Multiple mechanosensors may be involved in receiving mechanical signals.

Fig. 3

Computer simulation of Focal Adhesion Kinase (FAK). The figure shows three frames from a computer simulation of the change in conformation of the Focal Adhesion Kinase (FAK) molecule under load. Note that loading results in the exposure of an ATP-binding site (depicted in white). Courtesy of Ronald Kwon, C. Jacobs laboratory.

Fig. 4

Strain stimulation of MAPK is required for downstream gene regulation. The effect of strain to decrease RANKL (left graph) and increase eNOS (right graph) was complete blocked by the presence of an ERK1/2 kinase inhibitor (ERK-i). These results show that strain activation of ERK1/2 is necessary for the downstream effects in the bone stromal cell model. From (Rubin et al., 2003).

Fig. 5

Mechanical input improves trabecular bone microarchitecture. Fluorescent photomicrographs of a transverse section of proximal femur of adult (8 y) sheep, comparing a control animal (left) to an animal subject to 20 min per day of 30 Hz (cycles per second) of a low-level (0.3 g) mechanical vibration for one year (Rubin et al., 2001a). The large increase in trabecular bone density results in enhanced bone quality (Rubin et al., 2002b), achieved with tissue strains three orders of magnitude below those which cause damage to the tissue. These data suggest that specific mechanical parameters may represent a non-pharmacologic basis for the treatment of osteoporosis (Ward et al., 2004).