{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:21:36Z","timestamp":1790868096840,"version":"4.1.0"},"reference-count":52,"publisher":"The Company of Biologists","issue":"3-4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,3,8]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                  <jats:p>Long bone development depends on endochondral bone formation, a complex process requiring exquisite balance between hypertrophic cartilage (HC) formation and its ossification. Dysregulation of this process may result in skeletal dysplasias and heterotopic ossification. Endochondral ossification requires the precise orchestration of HC vascularization, extracellular matrix remodeling, and the recruitment of osteoclasts and osteoblasts. Matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and osteoclasts have all been shown to regulate endochondral ossification, but how their function interrelates is not known. We have investigated the functional relationship among these regulators of endochondral ossification, demonstrating that they have complementary but non-overlapping functions. MMP-9, VEGF and osteoclast deficiency all cause impaired growth plate ossification resulting in the accumulation of HC. VEGF mRNA and protein expression are increased at the MMP-9\u2212\/\u2212 growth plate, and VEGF activity contributes to endochondral ossification since sequestration of VEGF by soluble receptors results in further inhibition of growth plate vascularization and ossification. However, VEGF bioavailability is still limited in MMP-9 deficiency, as exogenous VEGF is able to rescue the MMP-9\u2212\/\u2212 phenotype, demonstrating that MMP-9 may partially, but not fully, regulate VEGF bioavailability. The organization of the HC extracellular matrix at the MMP-9\u2212\/\u2212 growth plate is altered, supporting a role for MMP-9 in HC remodeling. Inhibition of VEGF impairs osteoclast recruitment, whereas MMP-9 deficiency leads to an accumulation of osteoclasts at the chondro-osseous junction. Growth plate ossification in osteoclast-deficient mice is impaired in the presence of normal MMP-9 expression, indicating that other osteoclastic functions are also necessary. Our data delineate the complementary interplay between MMP-9, VEGF and osteoclast function that is necessary for normal endochondral bone formation and provide a molecular framework for investigating the molecular defects contributing to disorders of endochondral bone formation.<\/jats:p>","DOI":"10.1242\/dmm.004226","type":"journal-article","created":{"date-parts":[[2010,2,8]],"date-time":"2010-02-08T20:34:22Z","timestamp":1265661262000},"page":"224-235","source":"Crossref","is-referenced-by-count":100,"title":["Complementary interplay between matrix metalloproteinase-9, vascular endothelial growth factor and osteoclast function drives endochondral bone formation"],"prefix":"10.1242","volume":"3","author":[{"given":"Nathalie","family":"Ortega","sequence":"first","affiliation":[{"name":"Department of Anatomy"},{"name":"Present address: IPBS, CNRS UMR5089, Laboratoire de Biologie Vasculaire, 31077 Toulouse Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine and"},{"name":"Lung Biology Center, University of California, San Francisco, CA 94143, USA"},{"name":"Present address: Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin 130041, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Napoleone","family":"Ferrara","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zena","family":"Werb","sequence":"additional","affiliation":[{"name":"Department of Anatomy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiennu H.","family":"Vu","sequence":"additional","affiliation":[{"name":"Department of Medicine and"},{"name":"Lung Biology Center, University of California, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042500111593200_b1-0030224","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.bbrc.2005.07.145","article-title":"Vascular endothelial growth factor receptors in osteoclast differentiation and function","volume":"335","author":"Aldridge","year":"2005","journal-title":"Biochem Biophys Res Commun"},{"key":"2021042500111593200_b2-0030224","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/15537","article-title":"Perlecan is essential for cartilage and cephalic development","volume":"23","author":"Arikawa-Hirasawa","year":"1999","journal-title":"Nat Genet"},{"key":"2021042500111593200_b3-0030224","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/35036374","article-title":"Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis","volume":"2","author":"Bergers","year":"2000","journal-title":"Nat Cell Biol"},{"key":"2021042500111593200_b4-0030224","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1172\/JCI119316","article-title":"Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage","volume":"99","author":"Billinghurst","year":"1997","journal-title":"J Clin Invest"},{"key":"2021042500111593200_b5-0030224","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1053\/plac.2002.0890","article-title":"Regulation of trophoblastic gelatinases by proto-oncogenes","volume":"24","author":"Bischof","year":"2003","journal-title":"Placenta"},{"key":"2021042500111593200_b6-0030224","first-page":"84","article-title":"Merging the old skeletal biology with the new. 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