{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T21:59:38Z","timestamp":1781906378320,"version":"3.54.5"},"reference-count":75,"publisher":"SAGE Publications","issue":"13","license":[{"start":{"date-parts":[[2019,10,14]],"date-time":"2019-10-14T00:00:00Z","timestamp":1571011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100000069","name":"national institute of arthritis and musculoskeletal and skin diseases","doi-asserted-by":"publisher","award":["R01AR066782"],"award-info":[{"award-number":["R01AR066782"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"national institute of arthritis and musculoskeletal and skin diseases","doi-asserted-by":"publisher","award":["R01AR068835"],"award-info":[{"award-number":["R01AR068835"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"national center for advancing translational sciences","doi-asserted-by":"publisher","award":["UCLA CTSI UL1TR001881"],"award-info":[{"award-number":["UCLA CTSI UL1TR001881"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Dent Res"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:p>Neural EGFL-like 1 (Nell-1) is a well-studied osteogenic factor that has comparable osteogenic potency with the Food and Drug Administration\u2013approved bone morphogenic protein 2 (BMP-2). In this review, which aims to summarize the advanced Nell-1 research in the past 10 y, we start with the correlation of structural and functional relevance of the Nell-1 protein with the identification of a specific receptor of Nell-1, contactin-associated protein-like 4 (Cntnap4), for osteogenesis. The indispensable role of Nell-1 in normal craniofacial and appendicular skeletal development and growth was also defined by using the newly developed tissue-specific Nell-1 knockout mouse lines in addition to the existing transgenic mouse models. With the achievements on Nell-1\u2019s osteogenic therapeutic evaluations from multiple preclinical animal models for local and systemic bone regeneration, the synergistic effect of Nell-1 with BMP-2 on osteogenesis, as well as the advantages of Nell-1 as an osteogenic protein with antiadipogenic, anti-inflammatory, and provascularized characteristics over BMP-2 in bone tissue engineering, is highlighted, which lays the groundwork for the clinical trial approval of Nell-1. At the molecular level, besides the mitogen-activated protein kinase (MAPK) signaling pathway, we emphasize the significant involvement of the Wnt\/\u03b2-catenin pathway as well as the key regulatory molecules Runt-related transcription factor 2 (Runx2) in Nell-1-induced osteogenesis. In addition, the involvement of Nell-1 in chondrogenesis and its relevant pathologies have been revealed with the participation of the nuclear factor of activated T cells 1 (Nfatc1), Runx3, and Indian hedgehog (Ihh) signaling pathways, although the mechanistic insights of Nell-1\u2019s osteochondrogenic property will be continuously evolving. With this perspective, we elucidate some emerging and novel functional properties of Nell-1 in oral-dental and neural tissues that will be the frontiers of future Nell-1 studies beyond the context of bone and cartilage. As such, the therapeutic potential of Nell-1 continues to evolve and grow with continuous pursuit.<\/jats:p>","DOI":"10.1177\/0022034519882000","type":"journal-article","created":{"date-parts":[[2019,10,14]],"date-time":"2019-10-14T20:40:37Z","timestamp":1571085637000},"page":"1458-1468","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":41,"title":["Nell-1 Is a Key Functional Modulator in Osteochondrogenesis and Beyond"],"prefix":"10.1177","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6331-6983","authenticated-orcid":false,"given":"C.","family":"Li","sequence":"first","affiliation":[{"name":"Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Growth and Development, Section of 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