{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:00:52Z","timestamp":1791489652251,"version":"4.3.4"},"reference-count":90,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2012,9,18]],"date-time":"2012-09-18T00:00:00Z","timestamp":1347926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>X-linked hypophosphatemia (XLH\/HYP)\u2014with renal phosphate wasting, hypophosphatemia, osteomalacia, and tooth abscesses\u2014is caused by mutations in the zinc-metallopeptidase PHEX gene (phosphate-regulating gene with homologies to endopeptidase on the X chromosome). PHEX is highly expressed by mineralized tissue cells. Inactivating mutations in PHEX lead to distal renal effects (implying accumulation of a secreted, circulating phosphaturic factor) and accumulation in bone and teeth of mineralization-inhibiting, acidic serine- and aspartate-rich motif (ASARM)-containing peptides, which are proteolytically derived from the mineral-binding matrix proteins of the SIBLING family (small, integrin-binding ligand N-linked glycoproteins). Although the latter observation suggests a local, direct matrix effect for PHEX, its physiologically relevant substrate protein(s) have not been identified. Here, we investigated two SIBLING proteins containing the ASARM motif\u2014osteopontin (OPN) and bone sialoprotein (BSP)\u2014as potential substrates for PHEX. Using cleavage assays, gel electrophoresis, and mass spectrometry, we report that OPN is a full-length protein substrate for PHEX. Degradation of OPN was essentially complete, including hydrolysis of the ASARM motif, resulting in only very small residual fragments. Western blotting of Hyp (the murine homolog of human XLH) mouse bone extracts having no PHEX activity clearly showed accumulation of an \u223c35\u2009kDa OPN fragment that was not present in wild-type mouse bone. Immunohistochemistry and immunogold labeling (electron microscopy) for OPN in Hyp bone likewise showed an accumulation of OPN and\/or its fragments compared with normal wild-type bone. Incubation of Hyp mouse bone extracts with PHEX resulted in the complete degradation of these fragments. In conclusion, these results identify full-length OPN and its fragments as novel, physiologically relevant substrates for PHEX, suggesting that accumulation of mineralization-inhibiting OPN fragments may contribute to the mineralization defect seen in the osteomalacic bone characteristic of XLH\/HYP. \u00a9 2013 American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbmr.1766","type":"journal-article","created":{"date-parts":[[2012,9,18]],"date-time":"2012-09-18T16:13:39Z","timestamp":1347984819000},"page":"688-699","source":"Crossref","is-referenced-by-count":147,"title":["Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia"],"prefix":"10.1093","volume":"28","author":[{"given":"Nilana MT","family":"Barros","sequence":"first","affiliation":[{"name":"Departamento de Ci\u00eancias Exatas e da Terra, Universidade Federal de S\u00e3o Paulo, Diadema, Brazil"},{"name":"Departamento de Biof\u00edsica, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty","family":"Hoac","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel L","family":"Neves","sequence":"additional","affiliation":[{"name":"Departamento de Ci\u00eancias Exatas e da Terra, Universidade Federal de S\u00e3o Paulo, Diadema, Brazil"},{"name":"Departamento de Biof\u00edsica, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William N","family":"Addison","sequence":"additional","affiliation":[{"name":"Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego M","family":"Assis","sequence":"additional","affiliation":[{"name":"Departamento de Biof\u00edsica, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monzur","family":"Murshed","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, McGill University, Montreal, Canada"},{"name":"Faculty of Dentistry, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana K","family":"Carmona","sequence":"additional","affiliation":[{"name":"Departamento de Biof\u00edsica, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc D","family":"McKee","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Montreal, Canada"},{"name":"Faculty of Dentistry, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,9,18]]},"reference":[{"issue":"2","key":"2024020318431967400_bib1","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/ng1095-130","article-title":"A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets","volume":"11","author":"Francis","year":"1995","journal-title":"Nat Genet."},{"issue":"5","key":"2024020318431967400_bib2","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1096\/fasebj.11.5.9141502","article-title":"Mammalian membrane metallopeptidases: NEP, ECE, KELL, and PEX","volume":"11","author":"Turner","year":"1997","journal-title":"FASEB J."},{"issue":"2","key":"2024020318431967400_bib3","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1006\/jmbi.1999.3492","article-title":"Structure of human neutral endopeptidase (neprilysin) complexed with phosphoramidon","volume":"296","author":"Oefner","year":"2000","journal-title":"J Mol Biol."},{"issue":"4","key":"2024020318431967400_bib4","first-page":"F489","article-title":"Positional cloning of the PEX gene: new insights into the pathophysiology of X-linked hypophosphatemic rickets","volume":"273","author":"Econs","year":"1997","journal-title":"Am J Physiol."},{"issue":"2","key":"2024020318431967400_bib5","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1093\/ndt\/14.2.333","article-title":"X-linked hypophosphataemia: a homologous disorder in humans and mice","volume":"14","author":"Tenenhouse","year":"1999","journal-title":"Nephrol Dial Transplant."},{"issue":"9","key":"2024020318431967400_bib6","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1210\/me.2009-0085","article-title":"Novel regulators of Fgf23 expression and mineralization in Hyp bone","volume":"23","author":"Liu","year":"2009","journal-title":"Mol 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