{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:10:12Z","timestamp":1792606212031,"version":"4.5.0"},"reference-count":49,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2019,8,3]],"date-time":"2019-08-03T00:00:00Z","timestamp":1564790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81470762"],"award-info":[{"award-number":["81470762"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81530033"],"award-info":[{"award-number":["81530033"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81700995"],"award-info":[{"award-number":["81700995"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81500896"],"award-info":[{"award-number":["81500896"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The temporomandibular joint (TMJ), which is biomechanically related to dental occlusion, is often insulted by osteoarthritis (OA). This study was conducted to clarify the relationship between Indian hedgehog (Ihh) and parathyroid hormone receptor 1 (PTH1R) signaling in modulating the enhanced chondrocyte terminal differentiation in dental stimulated TMJ osteoarthritic cartilage. A gain- and loss-of-function strategy was used in an in vitro model in which fluid flow shear stress (FFSS) was applied, and in an in vivo model in which the unilateral anterior cross-bite (UAC) stimulation was adopted. Ihh and PTH1R signaling was modulated through treating the isolated chondrocytes with inhibitor\/activator and via deleting Smoothened (Smo) and\/or Pth1r genes in mice with the promoter gene of type 2 collagen (Col2-CreER) in the tamoxifen-inducible pattern. We found that both FFSS and UAC stimulation promoted the deep zone chondrocytes to undergo terminal differentiation, while cells in the superficial zone were robust. We demonstrated that the terminal differentiation process in deep zone chondrocytes promoted by FFSS and UAC was mediated by the enhanced Ihh signaling and declined PTH1R expression. The FFSS-promoted terminal differentiation was suppressed by administration of the Ihh inhibitor or PTH1R activator. The UAC-promoted chondrocytes terminal differentiation and OA-like lesions were rescued in Smo knockout, but were enhanced in Pth1r knockout mice. Importantly, the relieving effect of Smo knockout mice was attenuated when Pth1r knockout was also applied. Our data suggest a chondrocyte protective effect of suppressing Ihh signaling in TMJ OA cartilage which is dependent on PTH1R signaling.<\/jats:p>","DOI":"10.3390\/ijms20153797","type":"journal-article","created":{"date-parts":[[2019,8,5]],"date-time":"2019-08-05T03:25:22Z","timestamp":1564975522000},"page":"3797","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Inhibition of Ihh Reverses Temporomandibular Joint Osteoarthritis via a PTH1R Signaling Dependent Mechanism"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2388-2208","authenticated-orcid":false,"given":"Hongxu","family":"Yang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Military Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mian","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyun","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Lu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mianjiao","family":"Xie","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Rush University Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiqing","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/nm.3143","article-title":"Inhibition of TGF-\u03b2 signaling in subchondral bone mesenchymal stem cells attenuates osteoarthritis","volume":"19","author":"Zhen","year":"2013","journal-title":"Nat. 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