{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T05:56:54Z","timestamp":1775887014950,"version":"3.50.1"},"posted":{"date-parts":[[2025,1,24]]},"group-title":"Cell Biology","reference-count":64,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Weill-Marchesani syndrome (WMS) is characterized by severe short stature, short hands and feet (brachydactyly), joint contractures, tight skin, and heart valve, eye, and skin anomalies. Whereas recessive WMS is caused by mutations in\n                  <jats:italic>ADAMTS10<\/jats:italic>\n                  ,\n                  <jats:italic>ADAMTS17<\/jats:italic>\n                  , or\n                  <jats:italic>LTBP2<\/jats:italic>\n                  , dominant WMS is caused by mutations in\n                  <jats:italic>FBN1<\/jats:italic>\n                  (encoding fibrillin-1). Since bone growth is driven by chondrocyte proliferation and hypertrophy in the growth plates, the genetics of WMS suggests that the affected ECM proteins act within the same pathway to regulate chondrocyte and growth plate function. Here, we investigated the role of the secreted ADAMTS proteases ADAMTS10 and ADAMTS17 in growth plate function and ECM formation. We generated\n                  <jats:italic>Adamts10<\/jats:italic>\n                  ;\n                  <jats:italic>Adamts17<\/jats:italic>\n                  double knockout (DKO) mice, which showed significant postnatal lethality compared to single\n                  <jats:italic>Adamts10<\/jats:italic>\n                  or\n                  <jats:italic>Adamts17<\/jats:italic>\n                  KO mice. Importantly, we observed severe bone shortening DKO mice, which correlated with a narrower hypertrophic zone in their growth plates. ADAMTS17 substrates identified by N-terminomics and yeast two-hybrid screening identified the ECM proteins fibronectin and collagen VI (COL6). However, validation experiments did not reveal direct proteolysis of either fibronectin or COL6 by ADAMTS17. We then investigated ECM formation in primary ADAMTS10- and ADAMTS17-deficient skin fibroblasts and observed compromised fibronectin deposition concomitant with aberrant intracellular accumulation of fibrillin-1. These findings support a role for ADAMTS17 in ECM protein secretion and assembly. Collectively, our data suggest that ADAMTS10 and ADAMTS17 regulate bone growth by regulating chondrocyte hypertrophy or hypertrophic chondrocyte turnover. Mechanistically, ADAMTS17 appears to be a critical regulator of ECM protein secretion or pericellular matrix assembly, whereas ADAMTS10 likely modulates ECM formation at later stages, possibly regulating the spatio-temporal deposition of fibrillin isoforms.\n                <\/jats:p>","DOI":"10.1101\/2025.01.23.634616","type":"posted-content","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T06:10:16Z","timestamp":1737699016000},"source":"Crossref","is-referenced-by-count":1,"title":["Combined ADAMTS10 and ADAMTS17 inactivation exacerbates bone shortening and compromises extracellular matrix formation"],"prefix":"10.64898","author":[{"given":"Nandaraj","family":"Taye","sequence":"first","affiliation":[{"name":"Orthopedic Research Laboratories, Leni & Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4177-1114","authenticated-orcid":false,"given":"Stylianos Z.","family":"Karoulias","sequence":"additional","affiliation":[{"name":"Orthopedic Research Laboratories, Leni & Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zerina","family":"Balic","sequence":"additional","affiliation":[{"name":"Orthopedic Research Laboratories, Leni & Peter W. 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