Understanding Mechanobiology: Physical Therapists as a Force in Mechanotherapy and Musculoskeletal Regenerative Rehabilitation

Abstract

Achieving functional restoration of diseased or injured tissues is the ultimate goal of both regenerative medicine approaches and physical therapy interventions. Proper integration and healing of the surrogate cells, tissues, or organs introduced using regenerative medicine techniques are often dependent on the co-introduction of therapeutic physical stimuli. Thus, regenerative rehabilitation represents a collaborative approach whereby rehabilitation specialists, basic scientists, physicians, and surgeons work closely to enhance tissue restoration by creating tailored rehabilitation treatments. One of the primary treatment regimens that physical therapists use to promote tissue healing is the introduction of mechanical forces, or mechanotherapies. These mechanotherapies in regenerative rehabilitation activate specific biological responses in musculoskeletal tissues to enhance the integration, healing, and restorative capacity of implanted cells, tissues, or synthetic scaffolds. To become future leaders in the field of regenerative rehabilitation, physical therapists must understand the principles of mechanobiology and how mechanotherapies augment tissue responses. This perspective article provides an overview of mechanotherapy and discusses how mechanical signals are transmitted at the tissue, cellular, and molecular levels. The synergistic effects of physical interventions and pharmacological agents also are discussed. The goals are to highlight the critical importance of mechanical signals on biological tissue healing and to emphasize the need for collaboration within the field of regenerative rehabilitation. As this field continues to emerge, physical therapists are poised to provide a critical contribution by integrating mechanotherapies with regenerative medicine to restore musculoskeletal function.

Figure 1.

Mechanical forces direct cellular activities to induce tissue adaptation. Extrinsically and intrinsically generated mechanical forces load musculoskeletal tissues, with the characteristics of the resultant tissue forces being dependent on the ability of the tissue to resist those forces. Tissue forces are transmitted to the micromechanical environment of resident cells, with cellular mechanical properties influencing the characteristics of the cellular forces. Cells can modify their micromechanical environment via cytoskeletal rearrangement, which feeds back to alter cellular sensitivity to incoming forces. When cellular forces are sufficient, the cell initiates a molecular response, which ultimately alters synthesis or degradation of the extracellular matrix. The latter alters tissue mechanical properties, which feeds back to influence tissue forces.

Figure 2.

Common micromechanical stimuli to which musculoskeletal cells are exposed: (A) tension—pulling force that increases cell dimensions in the direction of pull; (B) compression—pushing force that decreases cell dimensions in the direction of push; (C) shear—parallel forces pushing or pulling in opposite directions to distort the cell; (D) hydrostatic pressure—pressure exerted by surrounding fluid that changes cell volume; (E) vibration—oscillating, reciprocal back-and-forth shaking of a cell; and (F) fluid shear—force created by the flow of fluid parallel to a cell membrane.

Figure 3.

Transducing mechanical signals into biochemical responses requires unique machinery. Forces are transmitted at the matrix/cell membrane interface where specialized complexes called focal adhesions form. Integrins span the plasma membrane, uniting the extracellular matrix with the internal actin cytoskeleton. Linker proteins, such as vinculin and talin, reinforce the structural integrity of the adhesion complex, and associated signaling effectors, including focal adhesion kinase (FAK) and Src, activate biochemical signaling pathways in response to force.

Figure 4.

A variety of extracellular receptors activate an overlapping network of mechanosensitive pathways. (A) Musculoskeletal cells can sense incoming mechanical signals using a diverse group of transmembrane mechanosensitive proteins (mechanosensors), including stretch-activated ion channels, cell-membrane spanning G-protein-coupled receptors, growth-factor receptors, and integrins. The mechanical stimulation of these proteins can lead to changes in their affinity to binding partners or ion conductivity. (B) Mechanical stimulation of the mechanosensors and alteration in their binding capacity or ion conductivity converts the mechanical signal into a biochemical signal (biochemical coupling) triggering intracellular signaling cascades. Many of the pathways overlap sharing signaling molecules. The convergence of the pathways results in the activation of select transcription factors, including nuclear factor of activated T cells (NFAT), nuclear factor-κβ (NF-κβ), activator protein 1 (AP1), GATA4 (a member of the transcription factor family characterized by the ability to bind the DNA sequence “GATA”), and signal transducer and activator of transcription factors (STATs). The transcription factors translocate to the nucleus and modulate the expression of a panel of mechanosensitive genes, including early growth response 1 (Egr1), lex1, Fos, Jun, and cyclo-oxygenase-2 (Cox2). Ultimately, the net sum of gene-expression reprogramming determines the functional response of the cell to a mechanical stimulus. Akt/PKB=protein kinase B; CaMK=calcium/calmodulin-dependent kinase; DAG=diacyl-glycerol; ERK=extracellular signal-regulated kinase; FAK=focal adhesion kinase; IP3=inositol triphosphate; JNKs=c-Jun N-terminal kinases; MEK=mitogen-activated protein kinase; MEKK=mitogen-activated protein kinase; MLCK=myosin light-chain kinase; NO=nitric oxide; NOS=nitric oxide synthase; PAK=p21-activated kinase; PI3K=phosphoinositide 3-kinase; PKC=protein kinase C; PLC=phospholipase C; Raf=rapidly accelerated fibrosarcoma kinase; Ras=rat sarcoma small GTPase.