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Fibrillin microfibrils are macromolecular ECM complexes serving structural and regulatory roles. In mice,\n                    <jats:italic>Fbn1<\/jats:italic>\n                    and\n                    <jats:italic>Fbn2,<\/jats:italic>\n                    encoding the major microfibrillar components, are strongly expressed during embryogenesis, but fibrillin-1 is the major component observed in adult tissue microfibrils. Here, analysis of\n                    <jats:italic>Adamts6<\/jats:italic>\n                    and\n                    <jats:italic>Adamts10<\/jats:italic>\n                    mutant mouse embryos, lacking these homologous secreted metalloproteases individually and in combination, along with in vitro analysis of microfibrils, measurement of ADAMTS6-fibrillin affinities and N-terminomics discovery of ADAMTS6-cleaved sites, identifies a proteostatic mechanism contributing to postnatal fibrillin-2 reduction and fibrillin-1 dominance. The lack of ADAMTS6, alone and in combination with ADAMTS10 led to excess fibrillin-2 in perichondrium, with impaired skeletal development defined by a drastic reduction of aggrecan and cartilage link protein, impaired BMP signaling in cartilage, and increased GDF5 sequestration in fibrillin-2-rich tissue. Although ADAMTS6 cleaves fibrillin-1 and fibrillin-2 as well as fibronectin, which provides the initial scaffold for microfibril assembly, primacy of the protease-substrate relationship between ADAMTS6 and fibrillin-2 was unequivocally established by reversal of the defects in\n                    <jats:italic>Adamts6<\/jats:italic>\n                    <jats:sup>-\/-<\/jats:sup>\n                    embryos by genetic reduction of\n                    <jats:italic>Fbn2<\/jats:italic>\n                    , but not\n                    <jats:italic>Fbn1<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.7554\/elife.71142","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T04:15:18Z","timestamp":1649909718000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.71142","source":"Crossref","is-referenced-by-count":33,"title":["Proteolysis of fibrillin-2 microfibrils is essential for normal skeletal development"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1891-3652","authenticated-orcid":true,"given":"Timothy J","family":"Mead","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03xjacd83","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomedical Engineering and Musculoskeletal Research Center, Cleveland Clinic Lerner Research Institute","place":["Cleveland, Ohio, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R","family":"Martin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03xjacd83","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomedical Engineering and Musculoskeletal Research Center, Cleveland Clinic Lerner Research Institute","place":["Cleveland, Ohio, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren 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