Cartilage-Specific Knockout of the Mechanosensory Ion Channel TRPV4 Decreases Age-Related Osteoarthritis.

Christopher J O’Conor,Di Chen,Nicole A Zelenski,Dianne Little,Wolfgang Liedtke,Sendhilnathan Ramalingam,Isaura Rigo,Farshid Guilak,Chia-Lung Wu,Amy L Mcnulty,Halei C Benefield

doi:10.1038/srep29053

Abstract

Osteoarthritis (OA) is a progressive degenerative disease of articular cartilage and surrounding tissues, and is associated with both advanced age and joint injury. Biomechanical factors play a critical role in the onset and progression of OA, yet the mechanisms through which physiologic or pathologic mechanical signals are transduced into a cellular response are not well understood. Defining the role of mechanosensory pathways in cartilage during OA pathogenesis may yield novel strategies or targets for the treatment of OA. The transient receptor potential vanilloid 4 (TRPV4) ion channel transduces mechanical loading of articular cartilage via the generation of intracellular calcium ion transients. Using tissue-specific, inducible Trpv4 gene-targeted mice, we demonstrate that loss of TRPV4-mediated cartilage mechanotransduction in adulthood reduces the severity of aging-associated OA. However, loss of chondrocyte TRPV4 did not prevent OA development following destabilization of the medial meniscus (DMM). These results highlight potentially distinct roles of TRPV4-mediated cartilage mechanotransduction in age-related and post-traumatic OA, and point to a novel disease-modifying strategy to therapeutically target the TRPV4-mediated mechanotransduction pathway for the treatment of aging-associated OA.

Highlights

Osteoarthritis (OA) is a common cause of pain and disability in the general population, affecting over 27 million people in the United States[1]
Col2a1-CreERT2+;Trpv4lox/lox and Col2a1-CreERT2−/−;Trpv4lox/lox (WT) littermates were induced with parental tamoxifen at 10 weeks of age. cartilage-specific Trpv4 knockout (cKO) mice did not demonstrate any overt differences in feeding, behavior, or gait compared to wild type (WT) mice, and the weights of the mice in both the aging and Destabilization of the medial meniscus (DMM) studies did not differ from WT mice (Fig. S1)
Chondrocytes from cKO mice maintained an equivalent level of basal signaling when compared to WT chondrocytes, but had no increase in signaling in response to GSK101 or hypo-osmotic stress, signifying a complete functional loss of transient receptor potential vanilloid 4 (TRPV4)-mediated Ca2+ signal transduction

Summary

Introduction

Osteoarthritis (OA) is a common cause of pain and disability in the general population, affecting over 27 million people in the United States[1]. OA is characterized by an imbalance of anabolic and catabolic activities by resident articular chondrocytes, which promotes cartilage tissue degradation[4,5,6] This loss of homeostatic balance is heavily influenced by biologic factors, such as aging[7] and inflammation[8], as well as biomechanical factors, such as altered joint kinematics related to obesity or following injury to the stabilizing menisci or ligaments of the knee[2]. In this regard, a better understanding of the pathways involved in biomechanically-mediated cartilage tissue homeostasis may provide important insights into the pathogenesis of OA, and provide potential molecular or physical targets for new OA therapeutics. Through the use of inducible and cartilage-specific transgenic mouse models, we have the ability to define the role of specific genes and pathways during disease progression in a temporal and tissue-specific fashion[28]

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