{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:49:30Z","timestamp":1787161770690,"version":"build-2736575974"},"reference-count":22,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T00:00:00Z","timestamp":1750464000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K13075"],"award-info":[{"award-number":["24K13075"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2025,6,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Inactivating mutations in the PHEX gene lead to X\u2010linked hypophosphatemia (XLH), which is characterized by impaired skeletal mineralization and low serum phosphate. Subsequent rickets and osteomalacia result in bone deformities and pseudofractures. A hallmark of XLH is an intrinsic defect in osteoblast function resulting in altered bone matrix composition typified by the local accumulation of extracellular matrix proteins and peptide fragments. PHEX is a membrane\u2010bound endopeptidase expressed in osteoblasts and osteocytes. Little is known about PHEX proteolytic substrates or the protein\u2013protein interactions governing PHEX function. Classical affinity purification approaches are challenging in studies of the extracellular environment. Here, we developed an approach for unbiased identification of the extracellular proximal interactome of PHEX in osteoblasts using proximity\u2010dependent biotin identification combined with affinity purification and mass spectrometry. By tagging the PHEX extracellular domain with BioID2 biotin ligase, we labeled and unveiled a PHEX proximity network consisting of 39 high\u2010confidence proteins. Notably, several candidates with documented roles in bone morphogenesis and matrix organization were identified. We validated interaction of PHEX with periostin, a bone\u2010matrix protein associated with collagen\u2010fibril organization, cell adhesion and cell migration. Co\u2010transfection experiments and cell\u2010free enzyme cleavage assays revealed proteolytic cleavage of secreted periostin by PHEX. In conclusion, BioID2 is a powerful strategy to explore cell\u2010matrix relationships in osteoblasts. These results present a novel map of the PHEX interactome and serve as a valuable resource for unraveling the mechanisms underlying PHEX function and XLH.<\/jats:p>","DOI":"10.1096\/fj.202500635rr","type":"journal-article","created":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T04:18:40Z","timestamp":1750479520000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Extracellular Matrix Proximity Biotinylation Identifies Periostin as a PHEX Proteolytic Substrate"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0597-6734","authenticated-orcid":false,"given":"Chirada","family":"Dusadeemeelap","sequence":"first","affiliation":[{"name":"Department of General Dentistry Faculty of Dentistry, Srinakharinwirot University  Bangkok Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8505-0431","authenticated-orcid":false,"given":"Takuma","family":"Matsubara","sequence":"additional","affiliation":[{"name":"Division of Molecular Signaling and Biochemistry Kyushu Dental University  Kitakyushu, Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6663-4327","authenticated-orcid":false,"given":"Shoichiro","family":"Kokabu","sequence":"additional","affiliation":[{"name":"Division of Molecular Signaling and Biochemistry Kyushu Dental University  Kitakyushu, Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8587-8028","authenticated-orcid":false,"given":"William N.","family":"Addison","sequence":"additional","affiliation":[{"name":"Division of Molecular Signaling and Biochemistry Kyushu Dental University  Kitakyushu, Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,21]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.7.6.573"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00008.2006"},{"issue":"2","key":"e_1_2_8_4_1","first-page":"722","article-title":"Aberrant Phex Function in Osteoblasts and Osteocytes Alone Underlies Murine X\u2010Linked Hypophosphatemia","volume":"118","author":"Yuan B.","year":"2008","journal-title":"Journal of Clinical 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