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TRPV4 as a therapeutic target for joint diseases

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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 Ca2+-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.

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Acknowledgments

This study is supported in part by the Arthritis Foundation and NIH grants AR48182, AR48852, AG15768, AR50245, AG46927, AG40868, DE018549, DE018549S1, DE024668, and AG047621.

Conflict of interest

Drs. McNulty, Leddy, and Liedtke declare that they have no conflicts of interest. Dr. Guilak is a founder and employee of Cytex Therapeutics, Inc.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Duke University Medical Center, DUMC 3093, Durham, NC, 27710, USA

    Amy L. McNulty, Holly A. Leddy & Farshid Guilak

  2. Department of Neurology and Duke University Clinics for Pain and Palliative Care, Duke University Medical Center, DUMC 2900, Durham, NC, 27710, USA

    Wolfgang Liedtke

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  1. Amy L. McNulty
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  2. Holly A. Leddy
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  3. Wolfgang Liedtke
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  4. Farshid Guilak
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Correspondence to Wolfgang Liedtke or Farshid Guilak.

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This article is published as part of the Special Issue on “TRP Channels as Drug Discovery Targets.”

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McNulty, A.L., Leddy, H.A., Liedtke, W. et al. TRPV4 as a therapeutic target for joint diseases. Naunyn-Schmiedeberg's Arch Pharmacol 388, 437–450 (2015). https://doi.org/10.1007/s00210-014-1078-x

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