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Destruction of perlecan at the COJ converts an avascular cartilage compartment into one that permits blood vessel infiltration and osteogenesis. Mutations in perlecan are associated with chondrodysplasia with widespread musculoskeletal and joint defects. This study elucidated novel signaling roles of perlecan core protein in endochondral bone formation and chondrocyte behavior. Perlecan subdomains were tested for chondrogenic properties in ATDC5 cells, a model for early chondrogenesis. A region within domain IV of perlecan (HSPG2 IV\u20103) was found to promote rapid prechondrocyte clustering. Introduction of the mutation (R3452Q) associated with the human skeletal disorder Schwartz\u2010Jampel syndrome limited HSPG2 IV\u20103\u2010induced clustering. HSPG2 IV\u20103 activity was enhanced when thermally unfolded, likely because of increased exposure of the active motif(s). HSPG2 IV\u20103\u2010induced clustering was accompanied by the deactivation of key components of the focal adhesion complex, FAK and Src, with increased messenger RNA (mRNA) levels of precartilage condensation markers Sox9 and N\u2010cadherin (\n<jats:italic>Cdh2<\/jats:italic>), and cartilage PCM components collagen II (\n<jats:italic>Col2a1<\/jats:italic>) and aggrecan (\n<jats:italic>Acan<\/jats:italic>). HSPG2 IV\u20103 reduced signaling through the ERK pathway, where loss of ERK1\/2 phosphorylation coincided with reduced FoxM1 protein levels and increased mRNA levels cyclin\u2010dependent kinase inhibitor 1C (Cdkn1c) and activating transcription factor 3 (\n<jats:italic>Atf3<\/jats:italic>), reducing cell proliferation. These findings point to a critical role for perlecan domain IV in cartilage development through triggering chondrocyte condensation.<\/jats:p>","DOI":"10.1002\/jcb.27521","type":"journal-article","created":{"date-parts":[[2018,9,11]],"date-time":"2018-09-11T04:41:58Z","timestamp":1536640918000},"page":"2138-2150","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Perlecan\/HSPG2: Signaling role of domain IV in chondrocyte clustering with implications for Schwartz\u2010Jampel Syndrome"],"prefix":"10.1002","volume":"120","author":[{"given":"Jerahme R.","family":"Martinez","sequence":"first","affiliation":[{"name":"Department of BioSciences Rice University Houston Texas"},{"name":"Department of Mechanical Engineering University of Delaware Newark Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian J.","family":"Grindel","sequence":"additional","affiliation":[{"name":"Department of BioSciences Rice University Houston Texas"},{"name":"Department of Diagnostic and Biomedical Sciences School of Dentistry, University of Texas Health Science Center at Houston Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsea M.","family":"Hubka","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Biomedical Sciences School of Dentistry, University of Texas Health Science Center at Houston Houston Texas"},{"name":"Department of Bioengineering Rice University Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George R.","family":"Dodge","sequence":"additional","affiliation":[{"name":"Translational Musculoskeletal Research Center, Corporal Michael J. 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