Mechanotransduction: Relevance to Physical Therapist Practice-Understanding Our Ability to Affect Genetic Expression Through Mechanical Forces.

Mechanotransduction, the mechanism by which mechanical perturbation influences genetic expression and cellular behavior, is an area of molecular biology undergoing rapid exploration and discovery. Cells are sensitive to forces such as shear, tension, and compression, and they respond accordingly through cellular proliferation, migration, tissue repair, altered metabolism, and even stem cell differentiation and maturation. The study of how cells sense and respond to mechanical stimulation is under robust expansion, with new scientific methods and technologies at our disposal. The application of these technologies to physical therapist practice may hold answers to some of our age-old questions while creating new avenues for our profession to optimize movement for societal health. Embracing this science as foundational to our profession will allow us to be valuable scientific collaborators with distinctive knowledge of the effects of loading. These partnerships will be key to augmenting the clinical utility of emerging therapies such as regenerative medicine, tissue engineering, and gene therapy. Collaboration with other scientific disciplines in these endeavors, along with the inclusion and application of these discoveries in our academic programs, will enhance the understanding of the impact of our practice on biologic and genetic processes. A basic understanding of mechanotransduction and its relevance to physical therapist practice is warranted to begin the conversation.

Pathophysiology of osteoarthritis: evidence against the viscoelastic theory.

OBJECTIVES: Whether changes in the hyaluronan moiety of synovial fluid are associated with osteoarthritis (OA) is unresolved experimentally, notwithstanding frequent statements in the literature that the disease leads to degraded hyaluronan. We evaluated this hypothesis by comparing the molecular weight and concentration of hyaluronan in synovial fluid from patients with and without OA. METHODS: Synovial fluid was obtained by needle aspiration from patients with advanced OA (Kellgren-Lawrence Grade IV) and from patients with no radiological or arthroscopic evidence of OA. The distribution of the molecular weight of hyaluronan was measured using both gel electrophoresis and size-exclusion chromatography, and hyaluronan concentration was determined by immunosorbent assay and differential refractometry. RESULTS: The distributions of molecular weight were highly variable within each group of patients; the average distributions, however, were identical in the 2 groups. The average concentration of hyaluronan also did not differ statistically between the 2 groups. CONCLUSIONS: We found no evidence of hyaluronan degradation in synovial fluid of patients with OA. Commonly expressed opinion in the literature to the contrary may have resulted from a failure to adequately consider the limitations of previous experimental studies.

Hyaluronan-binding receptors: possible involvement in osteoarthritis.

Our objectives were to compare the expression of the hyaluronan receptors CD44 and RHAMM in knee synovial tissue of patients with and without advanced osteoarthritis (OA). Both receptors were detected immunohistochemically; the staining appeared more intense in the tissues from the patients with advanced OA. Expression of CD44 and RHAMM were each significantly increased (p < 0.05) in synovial tissue from patients with OA, as determined by means of Western-blot analysis. The findings suggested that changes in levels of the HA-binding proteins might be implicated in the development or progression of OA.

Hyaluronan suppresses IL-1beta-induced metalloproteinase activity from synovial tissue.

Intraarticular injection of hyaluronan (viscosupplementation) is commonly used to treat knee pain from osteoarthritis. The therapeutic benefit might derive from hyaluronan inhibition of the activity of the cytokine-regulated catabolic enzymes that attack joint cartilage (matrix metalloproteinases). We tested the hypothesis that hyaluronan inhibited interleukin-1beta-induced matrix metalloproteinase activity secreted by explants of synovial tissue from patients with osteoarthritis and investigated the mechanism of the effect. Hyaluronan with a molecular mass of 12.8 MDa (number average) antagonized induced metalloproteinase activity in proportion to hyaluronan concentration in the clinically relevant range of 2 to 8 mg/mL. The effect was not attributable solely to molecular mass because 1.2-MDa hyaluronan produced comparable inhibition. Based on measurements involving hyaluronans of different average molecular masses, polydispersity and viscosity were similarly ruled out as primary responsible factors. The effect of hyaluronan on induced metalloproteinase activity was mediated partially by CD44, the principal cell surface receptor for hyaluronan. Hyaluronan inhibited interleukin-1beta-induced metalloproteinase production from osteoarthritic synovial tissue by a process that was not solely dependent on hyaluronan molecular mass but that was partly mediated by hyaluronan binding to CD44. The efficacy of viscosupplementation could be explained if hyaluronan also blocked catabolic enzyme activity in the joint.

Glycoproteins bound to ion channels mediate detection of electric fields: a proposed mechanism and supporting evidence.

The mechanism by which animals detect weak electric and magnetic fields has not yet been elucidated. We propose that transduction of an electric field (E) occurs at the apical membrane of a specialized cell as a consequence of an interaction between the field and glycoproteins bound to the gates of ion channels. According to the model, a glycoprotein mass (M) could control the gates of ion channels, where M > 1.4 x 10(-18)/E, resulting in a signal of sufficient strength to overcome thermal noise. Using the electroreceptor organ of Kryptopterus as a mathematical and experimental model, we showed that at the frequency of maximum sensitivity (10 Hz), fields as low as 2 microV/m could be detected, and that the observation could be explained if a glycoprotein mass of 0.7 x 10(-12) kg (a sphere 11 microm in diameter) were bound to channel gates. Antibodies against apical membrane structures in Kryptopterus blocked field transduction, which was consistent with the proposal that it occurred at the membrane surface. Although the target of the field was hypothesized to be an ion channel, the proposed mechanism can easily be extended to include other kinds of membrane proteins.