Mechanotransduction in musculoskeletal tissue regeneration: effects of fluid flow, loading, and cellular-molecular pathways

Abstract

While mechanotransductive signal is proven essential for tissue regeneration, it is critical to determine specific cellular responses to such mechanical signals and the underlying mechanism. Dynamic fluid flow induced by mechanical loading has been shown to have the potential to regulate bone adaptation and mitigate bone loss. Mechanotransduction pathways are of great interests in elucidating how mechanical signals produce such observed effects, including reduced bone loss, increased bone formation, and osteogenic cell differentiation. The objective of this review is to develop a molecular understanding of the mechanotransduction processes in tissue regeneration, which may provide new insights into bone physiology. We discussed the potential for mechanical loading to induce dynamic bone fluid flow, regulation of bone adaptation, and optimization of stimulation parameters in various loading regimens. The potential for mechanical loading to regulate microcirculation is also discussed. Particularly, attention is allotted to the potential cellular and molecular pathways in response to loading, including osteocytes associated with Wnt signaling, elevation of marrow stem cells, and suppression of adipotic cells, as well as the roles of LRP5 and microRNA. These data and discussions highlight the complex yet highly coordinated process of mechanotransduction in bone tissue regeneration.

Figure 1

Maintaining bone mass as a function of daily loading cycle number requires a certain strain threshold (microstrain). A curve fitting to the data shows daily loading cycle numbers from less than one cycle to greater than 100,000 cycles. The necessary strain to maintain bone mass is reduced as the daily loading cycle number increases.

Figure 2

Representative 3D μCT images of trabecular bone in distal femur. Graphs show mean ± SD values for bone volume fraction (BV/TV, %), connectivity density (Conn.D, 1/mm³), trabecular number (Tb.N, 1/mm), and separation (Tb.Sp, mm). MS at 50 Hz produced a significant change in all indices, compared to HLS. ^# P < 0.001 versus baseline; ⁺ P < 0.001 versus age-matched; *P < 0.05 versus HLS and 1 Hz MS; **P < 0.01 versus HLS and 1 Hz MS; ***P < 0.001 versus HLS and 1 Hz MS.

Figure 3

Representative 3D μCT images of trabecular bone in distal femur. Graphs show mean ± SD values for bone volume fraction (BV/TV, %), connectivity density (Conn.D, 1/mm³), trabecular number (Tb.N, 1/mm), and separation (Tb.Sp, mm). DHS at 2 Hz produced a significant change in all indices, compared to HLS. *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 4

Bone remodeling and its associated molecular pathways. The remodeling cycle of bone is composed of sequential phases including the activation of precursor cells, bone resorption by osteoclasts, bone formation by osteoblasts after reversal, and mineralization. The osteoblasts that are buried within the newly formed matrix become osteocytes. Other osteoblasts that rest on the bone surface become bone-lining cells.

Figure 5

Mechanical stimulation activates intracellular signaling pathways that converge with growth factors to activate transcription factors, which promotes bone formation. Perception of load (strain, “1”) triggers a number of intracellular responses including the release of PGE2, “2,” through a poorly understood mechanism into the lacunar-canalicular fluid where it can act in an autocrine and/or paracrine fashion. Connexin-43 hemichannels (CX43 HC) in this PGE2 and integrin proteins appear to be involved. Binding of PGE2 to its EP2 and/or EP4 receptor, “3,” leads to a downstream inhibition of GSK-3β, “5” (likely mediated by Akt, “4”) and the intracellular accumulation of free β-catenin, “6.” (Integrin activation can also lead to Akt activation and GSK-3β inhibition.) New evidence suggests that ER may participate in the nuclear translocation of β-catenin, “7,” which leads to changes in the expression of a number of key target genes “8.” One of the apparent consequences is the reduction in sclerostin and Dkk1, “9,” with increased expression of Wnt, “10”. The net result of these changes is to create a permissive environment for the binding of Wnt to LRP5-Fz and an amplification of the load signal, “11.”