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We show for the first time that cartilage-specific deletion of Creld2 results in disrupted endochondral ossification and short limbed dwarfism, whereas deletion of Creld2 in bone results in osteopenia, with a low bone density and altered trabecular architecture. Our study provides the first evidence that CRELD2 promotes the differentiation and maturation of skeletal cells by modulating noncanonical WNT4 signaling regulated by p38 MAPK. Furthermore, we show that CRELD2 is a novel chaperone for the receptor low-density lipoprotein receptor-related protein 1 (LRP1), promoting its transport to the cell surface, and that LRP1 directly regulates WNT4 expression in chondrocytes through TGF-\u03b21 signaling. Therefore, our data provide a novel link between an ER-resident chaperone and the essential WNT signaling pathways active during skeletal differentiation that could be applicable in other WNT-responsive tissues. \u00a9 2020 American Society for Bone and Mineral Research. \u00a9 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..<\/jats:p>","DOI":"10.1002\/jbmr.4010","type":"journal-article","created":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T09:30:36Z","timestamp":1584437436000},"page":"1452-1469","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["CRELD2 Is a Novel LRP1 Chaperone That Regulates Noncanonical WNT Signaling in Skeletal Development"],"prefix":"10.1093","volume":"35","author":[{"given":"Ella P","family":"Dennis","sequence":"first","affiliation":[{"name":"Biosciences Institute, Newcastle University, International Centre for Life Newcastle Upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah M","family":"Edwards","sequence":"additional","affiliation":[{"name":"Wellcome Trust Centre for Cell-Matrix Research University of Manchester Manchester 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