Mechanical Signals as Regulators of Cartilage Degeneration and Regeneration
In response to mechanical loading of the joint, the articular cartilage and chondrocytes are exposed to a complex array of stress, strain, fluid flow, osmotic changes, and other physical phenomena; however, under hyperphysiologic loading conditions, large deformations may lead to structural tissue damage, cell signaling, and pathologic anabolic and catabolic responses. The effect of mechanical stimuli on articular cartilage has been studied from morphologic and compositional perspectives, but an understanding of the molecular pathways involved in cellular signaling remains incomplete.
Although mechanical loading is necessary for normal cartilage maintenance, several in vivo studies suggest that abnormal mechanical forces appear to stimulate chondrocytes to produce inflammatory mediators,1 many of which are normally produced by macrophages during response to injury or infection.2 This response alters the delicate balance between anabolic and catabolic signaling, which can result in tissue damage and loss of function. Studies have further demonstrated that injurious compression can stimulate the production of reactive oxygen species and nitric oxide,3,4 which depolymerizes hyaluronic acid5 and kills chondrocytes6 and suggests that the antioxidative status of the cartilage might be essential for the prevention of mechanically induced cell death. Chondrocyte apoptosis with an altered pattern of aggrecan expression (along with changes in CD44 level and NITEGE) following injurious loading recently has been reported in mice,7,8 which can be reversed by inhibiting nuclear factor-κB (NF-κB) signaling.9 Furthermore, autophagy—a key factor for cell homeostasis—is also suppressed by mechanical loading.9 In addition to changes in the cartilage, the synovium can be affected by mechanical injury.7,8 Increased expression of inflammatory genes and NF-κB signaling lead to synovitis. Little is known about the molecular signaling in other tissues; additional research in this area is needed to fully understand the crosstalk among various knee joint tissues in conjunction with loading and injury.
The mechanisms by which mechanical factors alter the pathophysiology of chondrocytes or other cells within synovial joints likely involve complex interaction among genetic, epigenetic, and (transcription-level) molecular influences. Chondrocytes perceive physical signals from their environment using a variety of mechanisms, including ion channels, primary cilia, and integrin-mediated connections to the extracellular matrix that involve membrane cytoskeletal and intracellular deformation. Therefore, an improved understanding of the mechanisms by which cells sense and respond to mechanical signals may provide novel targets for the development of disease-modifying osteoarthritis drugs.10 In cases in which mechanotransduction is mediated directly via mechanically gated ion channels, mechanical stimulation causes an ionic flux, generally involving calcium ion (Ca2+) as an intracellular messenger. Given the relevance of mechanotransduction in health and disease, it is therefore surprising that the identification of specific mechanically gated ion channels has remained elusive, especially in mammals.
Recent evidence has confirmed the presence of several physically gated ion channels on the chondrocyte surface that may act as transducers of physiologic or pathologic mechanical loads.11 Of note, the transient receptor potential (TRP) family of ion channels have emerged as critical regulators of cellular responses to a wide range of physical and chemical signals, including mechanical loading, osmolarity, and temperature. In particular, the TRP vanilloid 4 (TRPV4) channel has been found to be expressed and functionally relevant in several musculoskeletal tissues, including cartilage, bone, and synovium.