Involvement of Transient Receptor Potential Vanilloid Channel 2 in the Induction of Lubricin and Suppression of Ectopic Endochondral Ossification in Mouse Articular Cartilage

Abstract

Objective. Transient receptor potential vanilloid channel 2 (TRPV2) is a Ca 2+ -permeable channel and plays a role in mediating intracellular Ca 2+ current via mechanical stimuli. This study was undertaken to examine the expression and role of TRPV2 in adult articular cartilage and the development of osteoarthritis (OA).Methods. We examined TRPV2 expression in mouse and human articular cartilage. We analyzed the development of OA in Col2a1-Cre ERt2 ;Trpv2 fl/fl mice and Trpv2 fl/fl littermates in the resection of the medial meniscus and medial collateral ligament model (n = 5 each), the destabilization of the medial meniscus model (n = 5 each), and the aging mouse model (n = 8-9 each). We examined marker protein expression in these joints, Ca 2+ influx by mechanical stimuli, and downstream pathways in vitro.Results. TRPV2 was expressed in mouse and human articular cartilage and ectopic ossification lesions. In all mouse models of OA examined, Col2a1-Cre ERt2 ;Trpv2 fl/fl mice were observed to have enhanced degradation of articular cartilage accompanied by decreased expression of lubricin/Prg4, and marked formation of periarticular ectopic ossification. Mechanical stress-induced Ca 2+ influx was decreased by Trpv2 knockout (KO). Prg4 induction by fluidflow shear stress was diminished in Trpv2-KO mouse chondrocytes, and this was mediated by the Ca 2+ /calmodulindependent protein kinase kinase-cyclic AMP response element binding protein axis. Hypertrophic differentiation was enhanced in Trpv2-KO mouse chondrocytes. Increased activity of calcineurin and nuclear translocation of nuclear factor in activated T cells 1 induced by fluid-flow shear stress or TRP agonist treatment was reversed by Trpv2 knockout.Conclusion. Our findings demonstrate regulation of articular cartilage by TRPV2 through Prg4 induction and suppression of ectopic ossification.

The superficial zone of articular cartilage

“…Prostaglandin E2 (PGE2) and parathyroid hormone-related peptide (PTHrP) are involved in the induction of PRG4 by mechanical loading, and the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)—cAMP response element binding protein 1 (CREB1) pathway mediates the processes [ 16 ]. Recently, we identified transient receptor potential vanilloid channel 2 (TRPV2) as one of the mechano-sensors involved in PRG4 induction [ 17 ]. TRPVs are Ca 2+ -permeable channels, and some members mediate intracellular Ca 2+ current via mechanical stimuli.…”

“…TRPVs are Ca 2+ -permeable channels, and some members mediate intracellular Ca 2+ current via mechanical stimuli. TPRV2 is expressed in the superficial and middle layers of normal articular cartilage in humans and mice, but its expression decreases with aging or OA progression [ 17 ]. Chondrocyte-specific knockout of Trpv2 results in accelerated OA in surgically-induced and aging models, accompanied by decreased expression of Prg4 [ 17 ].…”

“…TPRV2 is expressed in the superficial and middle layers of normal articular cartilage in humans and mice, but its expression decreases with aging or OA progression [ 17 ]. Chondrocyte-specific knockout of Trpv2 results in accelerated OA in surgically-induced and aging models, accompanied by decreased expression of Prg4 [ 17 ]. Mechanical stimulation-induced changes in intracellular Ca 2+ influx are markedly impaired in Trpv2 knockout chondrocytes [ 17 ].…”

“…Chondrocyte-specific knockout of Trpv2 results in accelerated OA in surgically-induced and aging models, accompanied by decreased expression of Prg4 [ 17 ]. Mechanical stimulation-induced changes in intracellular Ca 2+ influx are markedly impaired in Trpv2 knockout chondrocytes [ 17 ]. In vitro experiments using inhibitors indicate that calmodulin-dependent protein kinase kinase (CaMKK) and probably CaMKIV mediate PRG4 induction by CREB1 downstream of the TRPV2 pathway [ 17 ].…”

Mechanical Cues: Bidirectional Reciprocity in the Extracellular Matrix Drives Mechano-Signalling in Articular Cartilage

“…In addition to TRPV4, TRPV2 has been shown to be important in the maintenance of articular cartilage homeostasis [152]. Cartilage specific knockout of TRPV2 (Trpv2 −/− ) in mice resulted in the development of OA and three forms of mechanical stimulation (hypoosmotic stress, fluid flow, stretch) invoked Ca 2+ influx via up-regulation of lubricin and activation of CaMKK-Creb signalling which was abolished in Trpv2 −/− chondrocytes [152].…”