Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia

Boukpessi, Tchilalo; Hoac, Betty; Coyac, Benjamin R.; Léger, Thibaut; Garcia, Camille; Wicart, Philippe; Whyte, Michael P.; Glorieux, Francis H.; Linglart, Agnès; Miller, Catherine; McKee, Marc D.

doi:10.1016/j.bone.2016.11.019

Cited by 67 publications

(66 citation statements)

References 54 publications

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“…Moreover, these observations of OPN effects on dentin are supportive of findings pointing to increased OPN deposition in pathologies of dentin hypomineralization, e.g. X-linked hypophosphatemia [70–72]. A previous report employing energy dispersive spectroscopy analysis on Spp1 − / − mice found no differences in calcium or phosphorus content in teeth or alveolar bone [73].…”

Section: Discussionsupporting

confidence: 74%

Osteopontin regulates dentin and alveolar bone development and mineralization

Foster

Salmon

et al. 2018

Bone

107

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The periodontal complex is essential for tooth attachment and function and includes the mineralized tissues, cementum and alveolar bone, separated by the unmineralized periodontal ligament (PDL). To gain insights into factors regulating cementum-PDL and bone-PDL borders and protecting against ectopic calcification within the PDL, we employed a proteomic approach to analyze PDL tissue from progressive ankylosis knock-out (Ank) mice, featuring reduced PP, rapid cementogenesis, and excessive acellular cementum. Using this approach, we identified the matrix protein osteopontin (Spp1/OPN) as an elevated factor of interest in Ank mouse molar PDL. We studied the role of OPN in dental and periodontal development and function. During tooth development in wild-type (WT) mice, Spp1 mRNA was transiently expressed by cementoblasts and strongly by alveolar bone osteoblasts. Developmental analysis from 14 to 240days postnatal (dpn) indicated normal histological structures in Spp1 comparable to WT control mice. Microcomputed tomography (micro-CT) analysis at 30 and 90dpn revealed significantly increased volumes and tissue mineral densities of Spp1 mouse dentin and alveolar bone, while pulp and PDL volumes were decreased and tissue densities were increased. However, acellular cementum growth was unaltered in Spp1 mice. Quantitative PCR of periodontal-derived mRNA failed to identify potential local compensators influencing cementum in Spp1 vs. WT mice at 26dpn. We genetically deleted Spp1 on the Ank mouse background to determine whether increased Spp1/OPN was regulating periodontal tissues when the PDL space is challenged by hypercementosis in Ank mice. Ank; Spp1 double deficient mice did not exhibit greater hypercementosis than that in Ank mice. Based on these data, we conclude that OPN has a non-redundant role regulating formation and mineralization of dentin and bone, influences tissue properties of PDL and pulp, but does not control acellular cementum apposition. These findings may inform therapies targeted at controlling soft tissue calcification.

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Section: Discussionsupporting

confidence: 74%

Osteopontin regulates dentin and alveolar bone development and mineralization

Foster

Salmon

et al. 2018

Bone

107

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“…Additional complications of XLH include enthesopathy, osteoarthritis, pseudofractures, and dental abscesses. Severe dental disease is present in more than half of patients with XLH and is associated with abnormally mineralized dentin and cementum . Enthesopathy and osteoarthritis may severely limit range of motion and contribute to pain in patients with XLH .…”

Section: Fgf23 and Hypophosphatemia (Table )mentioning

confidence: 99%

“…Severe dental disease is present in more than half of patients with XLH and is associated with abnormally mineralized dentin and cementum. (37)(38)(39)(40)(41) Enthesopathy and osteoarthritis may severely limit range of motion and contribute to pain in patients with XLH. (42,43) The occurrence of spinal stenosis and its consequences in these patients is an under-recognized issue, impairing quality of life.…”

Section: Fgf23 and Hypophosphatemiamentioning

confidence: 99%

FGF23, Hypophosphatemia, and Emerging Treatments

2019

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FGF23 is an important hormonal regulator of phosphate homeostasis. Together with its co‐receptor Klotho, it modulates phosphate reabsorption and both 1α‐hydroxylation and 24‐hydroxylation in the renal proximal tubules. The most common FGF23‐mediated hypophosphatemia is X‐linked hypophosphatemia (XLH), caused by mutations in the PHEX gene. FGF23‐mediated forms of hypophosphatemia are characterized by phosphaturia and low or low‐normal calcitriol concentrations, and unlike nutritional rickets, these cannot be cured with nutritional vitamin D supplementation. Autosomal dominant and autosomal recessive forms of FGF23‐mediated hypophosphatemias show a similar pathophysiology, despite a variety of different underlying genetic causes. An excess of FGF23 activity has also been associated with a number of other conditions causing hypophosphatemia, including tumor‐induced osteomalacia, fibrous dysplasia of the bone, and cutaneous skeletal hypophosphatemia syndrome. Historically phosphate supplementation and therapy using analogs of highly active vitamin D (eg, calcitriol, alfacalcidol, paricalcitol, eldecalcitol) have been used to manage conditions involving hypophosphatemia; however, recently a neutralizing antibody for FGF23 (burosumab) has emerged as a promising treatment agent for FGF23‐mediated disorders. This review discusses the progression of clinical trials for burosumab for the treatment of XLH and its recent availability for clinical use. Burosumab may have potential for treating other conditions associated with FGF23 overactivity, but these are not yet supported by trial data. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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“…(20,21) Recently, we determined that osteopontin (OPN)-a potent inhibitor of mineralization that is highly expressed by osteoblasts and osteocytes in bone, and by odontoblasts and cementoblasts in teeth-is a physiologically relevant substrate for PHEX in these tissues. (22)(23)(24) OPN is a highly negatively charged, highly phosphorylated, intrinsically disordered secreted protein belonging to the small integrinbinding ligand N-linked glycoprotein (SIBLING) family. The high negative charge imparted by the abundance of the acidic amino acids aspartic acid and glutamic acid, and phosphoserine residues, in addition to its open, flexible, and disordered structure, allow OPN to bind extensively to ionic calcium, calcium in mineral precursor phases, and calcium in the hydroxyapatitelattice.…”

Section: Introductionmentioning

confidence: 99%

Genetic Ablation of Osteopontin in Osteomalacic Hyp Mice Partially Rescues the Deficient Mineralization Without Correcting Hypophosphatemia

Hoac

Østergaard

Wittig

et al. 2020

Journal of Bone and Mineral Research

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PHEX is predominantly expressed by bone and tooth-forming cells, and its inactivating mutations in X-linked hypophosphatemia (XLH) lead to renal phosphate wasting and severe hypomineralization of bones and teeth. Also present in XLH are hallmark hypomineralized periosteocytic lesions (POLs, halos) that persist despite stable correction of serum phosphate (P i) that improves bulk bone mineralization. In XLH, mineralization-inhibiting osteopontin (OPN, a substrate for PHEX) accumulates in the extracellular matrix of bone. To investigate how OPN functions in Hyp mice (a model for XLH), double-null (Hyp;Opn −/−) mice were generated. Undecalcified histomorphometry performed on lumbar vertebrae revealed that Hyp;Opn −/− mice had significantly reduced osteoid area/bone area (OV/BV) and osteoid thickness of trabecular bone as compared to Hyp mice, despite being as hypophosphatemic as Hyp littermate controls. However, tibias examined by synchrotron radiation micro-CT showed that mineral lacunar volumes remained abnormally enlarged in these double-null mice. When Hyp;Opn −/− mice were fed a high-P i diet, serum P i concentration increased, and OV/BV and osteoid thickness normalized, yet mineral lacunar area remained abnormally enlarged. Enpp1 and Ankh gene expression were increased in double-null mice fed a high-P i diet, potentially indicating a role for elevated inhibitory pyrophosphate (PP i) in the absence of OPN. To further investigate the persistence of POLs in Hyp mice despite stable correction of serum P i , immunohistochemistry for OPN on Hyp mice fed a high-P i diet showed elevated OPN in the osteocyte pericellular lacunar matrix as compared to Hyp mice fed a control diet. This suggests that POLs persisting in Hyp mice despite correction of serum P i may be attributable to the well-known upregulation of mineralization-inhibiting OPN by P i , and its accumulation in the osteocyte pericellular matrix. This study shows that OPN contributes to osteomalacia in Hyp mice, and that genetic ablation of OPN in Hyp mice improves the mineralization phenotype independent of systemic P i-regulating factors.

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Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia

Cited by 67 publications

References 54 publications

Osteopontin regulates dentin and alveolar bone development and mineralization

Osteopontin regulates dentin and alveolar bone development and mineralization

FGF23, Hypophosphatemia, and Emerging Treatments

Genetic Ablation of Osteopontin in Osteomalacic Hyp Mice Partially Rescues the Deficient Mineralization Without Correcting Hypophosphatemia

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