Mechanobiology in cellular, molecular, and tissue adaptation

Abstract

The use of mechanical biology and biomechanical signal transduction is a novel approach to attenuate biological tissue degeneration, whereas the understanding of specific cellular responses is critical to delineate the underlying mechanism. Dynamic mechanical signals with optimized loading signals, i.e., intensity and frequency, have been shown to have the potential to regulate adaptation and regeneration. Mechanotransduction pathways are of great interest in elucidating how mechanical signals produce such observed effects, including reduced tissue mass loss, increased healing and formation, and cell differentiation. While mechanobiology in the adaptation of cells and tissues is observed and recorded in the literature, its application in disease mechanism and treatment is under development. We would congratulate the opening of the Mechanobiology in Medicine journal, which provides an effective platform for advanced research in basic mechanotransduction and its translation in disease diagnosis, therapeutics, and beyond. This review aims to develop a cellular and molecular understanding of the mechanotransduction processes in tissue regeneration, which may provide new insights into disease mechanisms and the promotion of healing. Particular attention is allotted to the responses of mechanical loading, including potential cellular and molecular pathways, such as mechanotransduction associated with mechanotransduction pathways (e.g., Piezo ion channels and Wnt signaling), immune-response, neuron development, tissue adaptation and repair, and stem cell differentiation. Altogether, these discussed data highlight the complex yet highly coordinated mechanotransduction process in tissue regeneration.

Keywords: Biomechanics & mechanobiology; Bone adaptation; Cardiovascular adaptation; Cartilage regeneration; Loading frequency; Muscle atrophy; Osteopenia; Piezo 1; Ultrasound treatment.

Fig. 1

Bone remodeling and its associated molecular pathways [57].

Fig. 2

Mechanical loading, e.g., fluid shear stress, induced Wnt signaling activation [7]. The osteocyte perceives mechanical load applied to bone (ε) through an unknown mechanism, although fluid flow generated through the lacunar-canalicular system may be a critical component of this perception, ‘step 1’. Perception of load (strain) 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 paracrine fashion. Connexin-43 hemichannels (CX43 HC) in this PGE2 and integrin proteins appear to be involved. The binding of PGE2 to its EP2 and 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’ (which one or ones is unknown). The net result of these changes is to create a permissive environment for the binding of Wnt to Lrp5-Fz and amplification of the load signal, ‘11’.