title: Cartilage-Specific Knockout of the Mechanosensory Ion Channel TRPV4 Decreases Age-Related Osteoarthritis.
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.
authors.affiliation: Department of Pathology &Immunology, Washington University in St. Louis, Missouri, 63110, USA.|UNC/NCSU Joint Department of Biomedical Engineering, UNC School of Medicine, Chapel Hill, NC 27599, USA.|Department of Orthopaedic Surgery, Duke University Medical Center, Durham NC 27710, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Conor
authors.affiliation: Department of Orthopaedic Surgery, Duke University Medical Center, Durham NC 27710, USA.
authors.forename: Sendhilnathan
authors.initials: S
authors.lastname: Ramalingam
authors.affiliation: Department of Orthopaedic Surgery, Duke University Medical Center, Durham NC 27710, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Zelenski
authors.affiliation: UNC/NCSU Joint Department of Biomedical Engineering, UNC School of Medicine, Chapel Hill, NC 27599, USA.|Department of Orthopaedic Surgery, Duke University Medical Center, Durham NC 27710, USA.
authors.forename: Halei C
authors.initials: HC
authors.lastname: Benefield
authors.affiliation: Department of Orthopaedic Surgery, Duke University Medical Center, Durham NC 27710, USA.
authors.forename: Isaura
authors.initials: I
authors.lastname: Rigo
authors.affiliation: Department of Orthopaedic Surgery, Duke University Medical Center, Durham NC 27710, USA.
authors.forename: Dianne
authors.initials: D
authors.lastname: Little
authors.affiliation: Department of Orthopaedic Surgery, Washington University in St. Louis, Missouri, 63110, USA.|Shriners Hospitals for Children - St. Louis, St. Louis, Missouri 63110, USA.
authors.forename: Chia-Lung
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Rush University, Chicago, IL, 60612, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Neurology and Neurobiology, Duke University Medical Center, Durham NC 27710, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Liedtke
authors.affiliation: Department of Orthopaedic Surgery, Duke University Medical Center, Durham NC 27710, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: McNulty
authors.affiliation: Department of Orthopaedic Surgery, Washington University in St. Louis, Missouri, 63110, USA.|Shriners Hospitals for Children - St. Louis, St. Louis, Missouri 63110, USA.|UNC/NCSU Joint Department of Biomedical Engineering, UNC School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Farshid
authors.initials: F
authors.lastname: Guilak
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D002118:Calcium / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D040542:Mechanotransduction, Cellular; D008592:Menisci, Tibial / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D050916:TRPV Cation Channels / Q000172:deficiency / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D050916:TRPV Cation Channels; D053773:Transforming Growth Factor beta1; C486576:Trpv4 protein, mouse; D002118:Calcium