title: Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia.
abstract: Seven young patients with X-linked hypophosphatemia (XLH, having inactivating PHEX mutations) were discovered to accumulate osteopontin (OPN) at the sites of defective bone mineralization near osteocytes - the so-called hallmark periosteocytic (lacunar) "halos" of XLH. OPN was also localized in the pericanalicular matrix extending beyond the osteocyte lacunae, as well as in the hypomineralized matrix of tooth dentin. OPN, a potent inhibitor of mineralization normally degraded by PHEX, is a member of a family of acidic, phosphorylated, calcium-binding, extracellular matrix proteins known to regulate dental, skeletal, and pathologic mineralization. Associated with the increased amount of OPN (along with inhibitory OPN peptide fragments) in XLH bone matrix, we found an enlarged, hypomineralized, lacuno-canalicular network - a defective pattern of skeletal mineralization that decreases stiffness locally at: i) the cell-matrix interface in the pericellular environment of the mechanosensing osteocyte, and ii) the osteocyte's dendritic network of cell processes extending throughout the bone. Our findings of an excess of inhibitory OPN near osteocytes and their cell processes, and in dentin, spatially correlates with the defective mineralization observed at these sites in the skeleton and teeth of XLH patients. These changes likely contribute to the dento-osseous pathobiology of XLH, and participate in the aberrant bone adaptation and remodeling seen in XLH.
authors.affiliation: Faculty of Dentistry, McGill University, Montreal, QC, Canada; EA 2496, Laboratory of Orofacial Pathologies, Imaging and Biotherapies, School of Dentistry University Paris Descartes Sorbonne Paris Cité, Paris, France; AP-HP Department of Odontology, Charles Foix and Bretonneau Hospitals, Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism, Paris, France. Electronic address: Tchilalo.boukpessi@parisdescartes.fr.
authors.forename: Tchilalo
authors.initials: T
authors.lastname: Boukpessi
authors.affiliation: Faculty of Dentistry, McGill University, Montreal, QC, Canada.
authors.forename: Betty
authors.initials: B
authors.lastname: Hoac
authors.affiliation: Faculty of Dentistry, McGill University, Montreal, QC, Canada; EA 2496, Laboratory of Orofacial Pathologies, Imaging and Biotherapies, School of Dentistry University Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Coyac
authors.affiliation: Jacques Monod Institute, Proteomic Facility, University Paris Diderot Sorbonne Paris Cité, Paris, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Leger
authors.affiliation: Jacques Monod Institute, Proteomic Facility, University Paris Diderot Sorbonne Paris Cité, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Garcia
authors.affiliation: AP-HP Department of Pediatric Orthopedics, Necker Hospital, School of Medicine University Paris Descartes Sorbonne Paris Cité, Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Wicart
authors.affiliation: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Whyte
authors.affiliation: Shriners Hospital for Children, McGill University, Montreal, QC, Canada.
authors.forename: Francis H
authors.initials: FH
authors.lastname: Glorieux
authors.affiliation: AP-HP Department of Pediatric Endocrinology, Kremlin Bicêtre Hospital, School of Medicine University Paris Sud, Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism, Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Linglart
authors.affiliation: EA 2496, Laboratory of Orofacial Pathologies, Imaging and Biotherapies, School of Dentistry University Paris Descartes Sorbonne Paris Cité, Paris, France; AP-HP Department of Odontology, Charles Foix and Bretonneau Hospitals, Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chaussain
authors.affiliation: Faculty of Dentistry, McGill University, Montreal, QC, Canada; Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Montreal, QC, Canada. Electronic address: marc.mckee@mcgill.ca.
authors.forename: Marc D
authors.initials: MD
authors.lastname: McKee
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology*; D002648:Child; D003804:Dentin / Q000378:metabolism; D053098:Familial Hypophosphatemic Rickets / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010011:Osteocytes / Q000473:pathology; D053495:Osteopontin / Q000737:chemistry / Q000378:metabolism*; D040901:Proteomics; D014070:Tooth / Q000000981:diagnostic imaging / Q000473:pathology*
chemical_list: D053495:Osteopontin
keywords: Bone; Dentin; Mineralization; Osteocytic halos; Osteomalacia; PHEX; Rickets