X-linked hypophosphataemia (XLH) is an X-linked dominant disorder caused by mutations in PHEX (located at Xp22.1), which encodes a cell-surface-bound protein-cleavage enzyme (phosphate-regulating neutral endopeptidase PHEX), predominantly expressed in osteoblasts, osteocytes and teeth (odontoblasts and cementoblasts). XLH is the most common cause of inherited phosphate wasting, with an incidence of 3.9 per 100,000 live births and a prevalence ranging from 1.7 per 100,000 children to 4.8 per 100,000 persons (children and adults) 1-3. Although the pathogenesis of XLH is not fully understood, animal studies indicate that loss of Phex function results in enhanced secretion of the phosphaturic hormone fibroblast growth factor 23 (FGF23), with osteocytes being the primary source of FGF23 production 4. These effects explain most of the characteristic features of the disease, including renal phosphate wasting with consequent hypophosphataemia, diminished synthesis of active vitamin D (1,25(OH) 2 vitamin D), rickets, osteomalacia, odontomalacia and disproportionate short stature 4-6. Patients usually develop clinical symptoms during the first or second year of life. Early treatment with oral phosphate supplementation and active vitamin D heals rickets, limits dental abscess formation and prevents progressive growth failure, but in a substantial proportion of patients treatment is unsuccessful and/or associated with adverse effects (for example, hyper parathyroidism and nephrocalcinosis) 7,8. Up to two-thirds of children with XLH require lower limb surgery 9-12. Conventional therapy further stimulates FGF23 levels and thereby renal phosphate wasting, resulting in a vicious circle, which might limit its efficacy 6,13-15. Adult patients with XLH are at risk of complications such as early osteoarthritis, enthesopathies, spinal stenosis, pseudofractures and hearing loss, which might limit quality of life 16-18. In 2018, burosumab, a fully human monoclonal IgG1 antibody neutralizing FGF23, was approved by health authorities for the treatment of patients with
In children, hypophosphatemic rickets (HR) is revealed by delayed walking, waddling gait, leg bowing, enlarged cartilages, bone pain, craniostenosis, spontaneous dental abscesses, and growth failure. If undiagnosed during childhood, patients with hypophosphatemia present with bone and/or joint pain, fractures, mineralization defects such as osteomalacia, entesopathy, severe dental anomalies, hearing loss, and fatigue. Healing rickets is the initial endpoint of treatment in children. Therapy aims at counteracting consequences of FGF23 excess, i.e. oral phosphorus supplementation with multiple daily intakes to compensate for renal phosphate wasting and active vitamin D analogs (alfacalcidol or calcitriol) to counter the 1,25-diOH-vitamin D deficiency. Corrective surgeries for residual leg bowing at the end of growth are occasionally performed. In absence of consensus regarding indications of the treatment in adults, it is generally accepted that medical treatment should be reinitiated (or maintained) in symptomatic patients to reduce pain, which may be due to bone microfractures and/or osteomalacia. In addition to the conventional treatment, optimal care of symptomatic patients requires pharmacological and non-pharmacological management of pain and joint stiffness, through appropriated rehabilitation. Much attention should be given to the dental and periodontal manifestations of HR. Besides vitamin D analogs and phosphate supplements that improve tooth mineralization, rigorous oral hygiene, active endodontic treatment of root abscesses and preventive protection of teeth surfaces are recommended. Current outcomes of this therapy are still not optimal, and therapies targeting the pathophysiology of the disease, i.e. FGF23 excess, are desirable. In this review, medical, dental, surgical, and contributions of various expertises to the treatment of HR are described, with an effort to highlight the importance of coordinated care.
X-linked hypophosphatemia (XLH) is a rare genetic skeletal disease where increased phosphate wasting in the kidney leads to hypophosphatemia and prevents normal mineralization of bone and dentin. Here, we examined the periodontal status of 34 adults with XLH and separated them according to the treatment they received for hypophosphatemia. We observed that periodontitis frequency and severity were increased in adults with XLH and that the severity varied according to the hypophosphatemia treatment. Patients who benefited from an early and continuous vitamin D and phosphate supplementation during their childhood presented less periodontal attachment loss than patients with late or incomplete supplementation. Continued hypophosphatemia treatment during adulthood further improved the periodontal health. Extracted teeth from patients with late or incomplete supplementation showed a strong acellular cementum hypoplasia when compared with age-matched healthy controls. These results show that XLH disturbs not only bone and dentin formation but also cementum and that the constitutional defect of the attachment apparatus is associated with attachment loss.
Achondroplasia (ACH) is the most frequent form of dwarfism and is caused by gain-of-function mutations in the fibroblast growth factor receptor 3-encoding (FGFR3-encoding) gene. Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over many years, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity has yet to be evaluated. Here, we have reported that the pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the Fgfr3Y367C/+ mouse model of ACH. Moreover, we demonstrated that a low dose of NVP-BGJ398, injected subcutaneously, was able to penetrate into the growth plate of Fgfr3Y367C/+ mice and modify its organization. Improvements to the axial and appendicular skeletons were noticeable after 10 days of treatment and were more extensive after 15 days of treatment that started from postnatal day 1. Low-dose NVP-BGJ398 treatment reduced intervertebral disc defects of lumbar vertebrae, loss of synchondroses, and foramen-magnum shape anomalies. NVP-BGJ398 inhibited FGFR3 downstream signaling pathways, including MAPK, SOX9, STAT1, and PLCγ, in the growth plates of Fgfr3Y367C/+ mice and in cultured chondrocyte models of ACH. Together, our data demonstrate that NVP-BGJ398 corrects pathological hallmarks of ACH and support TKIs as a potential therapeutic approach for ACH.
In osteoclasts (OCs) podosomes are organized in a belt, a feature critical for bone resorption. Although microtubules (MTs) promote the formation and stability of the belt, the MT and/or podosome molecules that mediate the interaction of the two systems are not identified. Because the growing "plus" ends of MTs point toward the podosome belt, plus-end tracking proteins (؉TIPs) might regulate podosome patterning. Among the ؉TIPs, EB1 increased as OCs matured and was enriched in the podosome belt, and EB1-positive MTs targeted podosomes. Suppression of MT dynamic instability, displacement of EB1 from MT ends, or EB1 depletion resulted in the loss of the podosome belt. We identified cortactin as an Src-dependent interacting partner of EB1. Cortactin-deficient OCs presented a defective MT targeting to, and patterning of, podosomes and reduced bone resorption. Suppression of MT dynamic instability or EB1 depletion increased cortactin phosphorylation, decreasing its acetylation and affecting its interaction with EB1. Thus, dynamic MTs and podosomes interact to control bone resorption.
Hypophosphatasia is a rare disorder due to a mutation in the ALPL gene encoding the alkaline phosphatase (ALP) leading to a diminished activity of the enzyme in bone, liver, and kidney. Hypophosphatasia is a heterogeneous disease, ranging from extreme life-threatening forms revealed at birth in young infants presenting with severely impaired bone mineralization, seizures, and hypercalcemia, to young adults with premature exfoliation of their teeth without any other symptom. We will review the challenges of the clinical, biochemical, radiological, and genetic diagnosis. Schematically, the diagnosis relies on low ALP levels and, in most cases, on the genetic defect in the ALPL gene. An enzyme replacement therapy is now developed for hypophosphatasia; early results in the severe form of the disease are extremely encouraging. However, multidisciplinary care remains the core of treatment of hypophosphatasia encompassing nutritional support, adjustment of calcium and phosphate intake, monitoring of vitamin D levels, careful and personalized physical therapy, and regular dental monitoring and care.
FGFR3 gain-of-function mutations lead to both chondrodysplasias and craniosynostoses. Achondroplasia (ACH), the most frequent dwarfism, is due to an FGFR3-activating mutation which results in impaired endochondral ossification. The effects of the mutation on membranous ossification are unknown. Fgfr3(Y367C/+) mice mimicking ACH and craniofacial analysis of patients with ACH and FGFR3-related craniosynostoses provide an opportunity to address this issue. Studying the calvaria and skull base, we observed abnormal cartilage and premature fusion of the synchondroses leading to modifications of foramen magnum shape and size in Fgfr3(Y367C/+) mice, ACH and FGFR3-related craniosynostoses patients. Partial premature fusion of the coronal sutures and non-ossified gaps in frontal bones were also present in Fgfr3(Y367C/+) mice and ACH patients. Our data provide strong support that not only endochondral ossification but also membranous ossification is severely affected in ACH. Demonstration of the impact of FGFR3 mutations on craniofacial development should initiate novel pharmacological and surgical therapeutic approaches.
In addition to the numerous roles of histamine in both the immune and nervous systems, previous studies have suggested that this bioamine might also be involved in bone metabolism. Following our observations of impaired bone resorption in ovariectomized rats after histamine receptor antagonist treatment, we focused in this study on osteoclasts and osteoclast precursors. We looked for a direct action of histamine on these cells using both in vivo and in vitro approaches. In vivo, we triggered a remodeling sequence in rat mandibular bone and treated the animals with either histamine or histamine receptor antagonists. Histamine was shown to increase the number of osteoclasts and osteoclast precursors whereas antagonists of histamine receptor-1 and -2 decreased both osteoclast recruitment and resorption. In vitro, spleen cells from histamine-deficient mice were treated with receptor activator for nuclear factor kappa B ligand and macrophage colony stimulating factor, giving rise to both reduced numbers of osteoclasts and decreased resorption on dentin slices. Histamine enhanced resorption in these cultures in a dose-dependent manner. In addition, we identified osteoclast precursors as a source of histamine. In contrast, histamine increased the receptor activator for nuclear factor kappa B ligand/osteoprotegerin ratio in primary osteoblasts that did not secrete histamine. We observed a differential expression of histamine receptor-1 and -2 mRNAs in both primary osteoclasts and osteoblasts, confirming their functional roles with selective antagonists. Thus, histamine acts directly on osteoclasts, osteoclast precursors, and osteoblasts, promoting osteoclastogenesis through autocrine/paracrine mechanisms.
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