Wnt7a Inhibits IL-1β Induced Catabolic Gene Expression and Prevents Articular Cartilage Damage in Experimental Osteoarthritis.
Wnt7a is a protein that plays a critical role in skeletal development. However, its effect on cartilage homeostasis under pathological conditions is not known. In this study, we found a unique inverse correlation between Wnt7a gene expression and that of MMP and IL-1β in individual human OA cartilage specimens. Upon ectopic expression in primary human articular chondrocytes, Wnt7a inhibited IL-1β-induced MMP and iNOS gene expression. Western blot analysis indicated that Wnt7a induced both canonical Wnt signaling and NFAT and Akt non-canonical signaling. Interestingly, inhibiting the canonical and Akt pathway did not affect Wnt7a activity. However, inhibiting the NFAT pathway impaired Wnt7a's ability to inhibit MMP expression, suggesting that Wnt7a requires NFAT signaling to exert this function. In vivo, intraarticular injection of lentiviral Wnt7a strongly attenuated articular cartilage damage induced by destabilization of the medial meniscus (DMM) OA-inducing surgery in mice. Consistently, Wnt7a also inhibited the progressive increase of joint MMP activity in DMM animals. These results indicate that Wnt7a signaling inhibits inflammatory stimuli-induced catabolic gene expression in human articular chondrocytes and is sufficient to attenuate MMP activities and promote joint cartilage integrity in mouse experimental OA, demonstrating a novel effect of Wnt7a on regulating OA pathogenesis.
Program in Cellular, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA.|Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA 02111, USA.
Averi L
AL
Gibson
Program in Cellular, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA.|Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA 02111, USA.
Carrie K
CK
Hui Mingalone
Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA 02111, USA.
Andrea T
AT
Foote
Program in Cellular, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA.|Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA 02111, USA.
Tomoya
T
Uchimura
Department of Rheumatology, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
Ming
M
Zhang
Program in Cellular, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA.|Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA 02111, USA.|Department of Orthopedics, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
Li
L
Zeng
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D002384:Catalysis; D019902:Chondrocytes / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010003:Osteoarthritis / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D055114:X-Ray Microtomography
D053583:Interleukin-1beta; C092778:WNT7A protein, human; D051153:Wnt Proteins; D003094:Collagen