TRPV4 as a therapeutic target for joint diseases

Abstract

Biomechanical factors play a critical role in regulating the physiology as well as the pathology of multiple joint tissues and have been implicated in the pathogenesis of osteoarthritis. Therefore, the mechanisms by which cells sense and respond to mechanical signals may provide novel targets for the development of disease-modifying osteoarthritis drugs (DMOADs). Transient receptor potential vanilloid 4 (TRPV4) is a Ca(2+)-permeable cation channel that serves as a sensor of mechanical or osmotic signals in several musculoskeletal tissues, including cartilage, bone, and synovium. The importance of TRPV4 in joint homeostasis is apparent in patients harboring TRPV4 mutations, which result in the development of a spectrum of skeletal dysplasias and arthropathies. In addition, the genetic knockout of Trpv4 results in the development of osteoarthritis and decreased osteoclast function. In engineered cartilage replacements, chemical activation of TRPV4 can reproduce many of the anabolic effects of mechanical loading to accelerate tissue growth and regeneration. Overall, TRPV4 plays a key role in transducing mechanical, pain, and inflammatory signals within joint tissues and thus is an attractive therapeutic target to modulate the effects of joint diseases. In pathological conditions in the joint, when the delicate balance of TRPV4 activity is altered, a variety of different tools could be utilized to directly or indirectly target TRPV4 activity.

Fig. 1. Mechanisms by which TRPV4 mutations may lead to skeletal dysplasias

Excess Ca²⁺ enters through the mutant channel, causing phosphorylation of cyclic AMP response element binding protein (CREB), which binds the cyclic AMP response element (CRE) and causes follistatin (FST) transcription. Follistatin inhibits BMP activity, which prevents growth plate chondrocytes from undergoing hypertrophy and forming bone, thus leading to skeletal dysplasia. Reprinted from (Leddy et al., 2014b).

Fig. 2. TRPV4 regulates chondrocyte metabolic response to loading

Daily osmotic loading or GSK1016790A treatment increased proteoglycan content (shown by Safranin-O staining) and type II collagen content (shown by immunohistochemistry) after four weeks of culture. Scale bar = 2mm. Reprinted from (O'Conor et al., 2014).

Fig. 3. Sex-specific differences in the role of Trpv4 in the skeleton

Male Trpv4^−/− mice had increased bone mass, increased subchondral bone volume, and diminished trabecular bone density. Representative frontal (left) and sagittal (right) microCT views of the intact knee of male wildtype (A, B) and Trpv4^−/− (C, D) mice. (A, C) 4 month old mice. (B, D) 12 month old mice. Scale bar = 1mm. Significant enlargement of the calcified regions of the menisci was observed, as well as that of the patella and condylar sesamoid bones (arrows) in Trpv4^−/− mice at 12 months. Reprinted from (Clark et al., 2010).

Fig. 4. Attenuation of bite force in response to TMJ inflammation depends on Trpv4

(A) The attenuation of bite force in response to complete Freund’s adjuvant (CFA) is dependent on Trpv4 in both sexes. There is not a measurable reduction in bite force when injecting incomplete Freud’s adjuvant (IFA) as a control. ***p<0.001, **p<0.01, *p<0.05 by one-way ANOVA with Tukey post hoc test. (B) The systemic application of the TRPV4-specific inhibitor, HC-067047, applied 24h after TMJ injection with CFA attenuates the bite force. One hour after application of HC-067047, the attenuation is similar to the level observed in Trpv4^−/− mice. However, at 3 hours the compound loses its effect and at 5 hours and 7 hours it is no longer different from vehicle-injected. HC-067047 did not alter the bite force in Trpv4^−/− mice, indicating a lack of off-target effects. ** p<0.01, *p<0.05 versus vehicle-treated by two-tail t-test. Reprinted from (Chen et al., 2013).

Fig. 5. Targeting TRPV4 for musculoskeletal disease

TRPV4 expression levels and/or activity can be altered directly with chemical agonists/antagonists, interfering RNAs, biological activators or blockers, such as TRPV4-binding antibodies, or by acting on peripheral targets that affect TRPV4. Altered TRPV4 activity/expression could impact osteoarthritis, bone resorption diseases, skeletal dsyplasias, and arthritis pain. In addition, TRPV4 can be targeted in a tissue engineering context to enhance matrix synthesis by simulating loading conditions or to increase differentiation of stem cells into chondrocytes or osteocytes.