Controlling mechanical signal transduction to treat osteoarthritis Abstract The TRPV4 calcium (Ca++) permeable ion channel has been shown to be expressed and functional in chondrocytes, the cells responsible for the maintenance of cartilage in weight-bearing joints. Trauma of joints with subsequent damage of cartilage, as well as chronically increased joint load as in obesity, are known predisposing factors for development of osteoarthritis, a disease with major impact - health, socioeconomic - in the US and many other countries. Previous work, including our own, unambiguously links TRPV4 to osteoarthritis. TRPV4 appears to be a necessary and critical regulator of chondrocytes'response to mechanical loading in both health and disease. Thus, we propose to use selective modulators of TRPV4 to attenuate development of osteoarthritis. In this respect, we have developed several small molecule compounds that serve as selective agonists and antagonists of the channel. Therefore we have the ability in effect to turn on and off the activity of the channel, providing a means of "tuning" the chondrocytes'sensitivity to mechanical loading. In this collaborative small business-academia effort we will explore the effects of these novel compounds in cellular and animal models of articular injury. The goal is explicitly to identify TRPV4 modulators that can effectively tune signal transduction in chondrocytes so that the compounds will attenuate injury to chondrocytes and cartilage. We will assess whether these compounds have beneficial effects in an animal model of post-traumatic joint injury by mechanism of a temporary tuning of osmo-mechanotransduction, which ultimately will result in chondroprotection. The development of small molecule agonists and antagonists of TRPV4 has important implications in the treatment of cartilage diseases such as osteoarthritis. As academia- small business collaborators, we envision to develop these compounds jointly and move them forward towards clinical trials. Beyond single-trauma induced joint injury, we also see as a clear target the more chronic joint injury facilitated by obesity.
Degenerative and post-traumatic osteoarthritis are human diseases with high relevance for US public health, with increasing impact due to a non-linear increase in prevalence. In this application we describe an approach based on availability of a manageable set of TRPV4-modulating compounds, and propose to test these compounds in cellular and animal models of articular injury. Our proposed academia-small business collaboration will position us favorably to move forward with well-characterized and effective small molecules, so that chondrocytes'osmo-mechanotransduction after articular injury can be tuned in order to provide chemical chondroprotection, a hitherto unrealized therapeutic principle.
|McNulty, Amy L; Leddy, Holly A; Liedtke, Wolfgang et al. (2015) TRPV4 as a therapeutic target for joint diseases. Naunyn Schmiedebergs Arch Pharmacol 388:437-50|