[Rickets/Osteomalacia. FGF23-related hypophosphatemic rickets/osteomalacia.]

FGF23 is a hormone that reduces blood phosphate level. Excessive actions of FGF23 result in several kinds of hypophosphatemic rickets/osteomalacia such as X-linked hypophosphatemic rickets and tumor-induced osteomalacia. It is not clear how excessive actions of FGF23 are induced in these diseases. The inhibition of excessive FGF23 actions is a promising new treatment for FGF23-related hypophosphatemic rickets/osteomalacia.

Molecular analysis of enthesopathy in a mouse model of hypophosphatemic rickets.

The bone tendon attachment site known as the enthesis comprises a transitional zone between bone and tendon, and plays an important role in enabling movement at this site. X-linked hypophosphatemia (XLH) is characterized by impaired activation of vitamin D, elevated serum FGF23 levels and low serum phosphate levels, which impair bone mineralization. Paradoxically, an important complication of XLH is mineralization of the enthesis (enthesopathy). Studies were undertaken to identify the cellular and molecular pathways important for normal post-natal enthesis maturation and to examine their role during the development of enthesopathy in mice with XLH (Hyp). The Achilles tendon entheses of Hyp mice demonstrate an expansion of hypertrophic-appearing chondrogenic cells by P14. Post-natally, cells in wild-type and Hyp entheses similarly descend from scleraxis- and Sox9-expressing progenitors; however, Hyp entheses exhibit an expansion of Sox9-expressing cells, and enhanced BMP and IHH signaling. These results support a role for enhanced BMP and IHH signaling in the development of enthesopathy in XLH.

Dentoalveolar Abscesses Not Associated with Caries or Trauma: A Diagnostic Hallmark of Hypophosphatemic Rickets Initially Misdiagnosed as Hypochondroplasia.

Hypophosphatemic rickets is a rare genetic disorder involving the regulation of fibroblast growth factor 23 (FGF23), a phosphaturic agent, clinically showing bowing of the legs, short stature and dentoalveolar abscesses. A 7-year-old boy, with previous hypochondroplasia diagnosis, was referred to our pediatric dentistry clinic presenting short stature, bone deformities and sinus tracts at deciduous teeth apex levels not related with trauma, restorations or dental caries. After deciduous teeth extraction, due to root resorption and mobility, light microscopy exhibited typical hypophosphatemic dentin, and micro-computed tomography revealed tubular clefts and porosities throughout the teeth. Laboratory tests confirmed the HR diagnosis, after which the treatment was initiated.

The vitamin D receptor functions as a transcription regulator in the absence of 1,25-dihydroxyvitamin D3.

The vitamin D receptor (VDR) is a critical mediator of the biological actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). As a nuclear receptor, ligand activation of the VDR leads to the protein's binding to specific sites on the genome that results in the modulation of target gene expression. The VDR is also known to play a role in the hair cycle, an action that appears to be 1,25(OH)2D3-independent. Indeed, in the absence of the VDR as in hereditary 1,25-dihydroxyvitamin D resistant rickets (HVDRR) both skin defects and alopecia emerge. Recently, we generated a mouse model of HVDRR without alopecia wherein a mutant human VDR lacking 1,25(OH)2D3-binding activity was expressed in the absence of endogenous mouse VDR. While 1,25(OH)2D3 failed to induce gene expression in these mice, resulting in an extensive skeletal phenotype, the receptor was capable of restoring normal hair cycling. We also noted a level of secondary hyperparathyroidism that was much higher than that seen in the VDR null mouse and was associated with an exaggerated bone phenotype as well. This suggested that the VDR might play a role in parathyroid hormone (PTH) regulation independent of 1,25(OH)2D3. To evaluate this hypothesis further, we contrasted PTH levels in the HVDRR mouse model with those seen in Cyp27b1 null mice where the VDR was present but the hormone was absent. The data revealed that PTH was indeed higher in Cyp27b1 null mice compared to VDR null mice. To evaluate the mechanism of action underlying such a hypothesis, we measured the expression levels of a number of VDR target genes in the duodena of wildtype mice and in transgenic mice expressing either normal or hormone-binding deficient mutant VDRs. We also compared expression levels of these genes between VDR null mice and Cyp27b1 null mice. In a subset of cases, the expression of VDR target genes was lower in mice containing the VDR as opposed to mice that did not. We suggest that the VDR may function as a selective suppressor/de-repressor of gene expression in the absence of 1,25(OH)2D3.

The in vivo role of DMP-1 and serum phosphate on bone mineral composition.

Human DMP1 mutations or Dmp1-null (KO) mice display hypophosphatemia rickets, suggesting a causative role of low phosphate (P) in development of osteomalacia. To address the direct contribution of P to the in vivo bone mineralization we analyzed the properties of femurs obtained from Dmp1 null mice and wild type (WT) mice under a normal or high phosphorous (HiP) diet using combined assays, including histological examination, micro computed tomography (µCT), X-ray absorption near edge structure (XANES) spectroscopy and Raman spectroscopy. Histology and XANES indicate that WT mice have phosphate coordinated with Ca in the form of hydroxyapatite and tricalcium phosphate, while the KO mice have poorly coordinated soluble phosphates in their structure in both the normal and HiP diets. Raman spectroscopy and XANES indicate a higher carbonate/phosphate ratio and a low mineral/matrix ratio in the osteoid clusters in the KO femurs, which was only partially improved by HiP diets. Thus, we conclude that the hypophosphatemia induced osteomalacia phenotype in Dmp1 KO mice is contributed by at least two factors: the low Pi level and the DMP1 local function in mineralization.

Polyostotic osteolysis and hypophosphatemic rickets with elevated serum fibroblast growth factor 23: A case report.

We report on a boy who presented with hypophosphatemic rickets with elevated serum fibroblast growth factor 23 (FGF23) and polyostotic osteolytic lesions at age 2 years. Tumor-induced hypophosphatemic rickets was suspected; however, bone biopsy for osteolytic changes revealed no tumorous change, except for irregularly dilated vessels associated with osteoclasts and fibrous proliferation. Venous sampling failed to point to FGF23-producing foci. After alfacalcidol and phosphate supplementation, the rachitic skeletal changes improved, but FGF23 increased and new osteolytic lesions developed. Serum levels of neopterin and a few cytokines, including plasma transforming growth factor-ß and soluble tumor necrosis factor receptor type II, were elevated. At age 4 years, high doses of phosphate resulted in increased serum phosphate levels, decreased neopterin and cytokines, decreased FGF23, and stabilization of osteolysis. We excluded germline mutations in PHEX, FGF23, DMP1, and ENPP1 (genes for hereditary hypophosphatemic rickets) and somatic mutations in the GNAS and HRAS/KRAS (the disease-causing genes for McCune-Albright syndrome and linear nevus sebaceous syndrome, respectively). We could not perform octreotide scintigraphy or fluorodeoxyglucose-positron emission tomography, and thus could not completely exclude occult FGF23-producing tumors. However, considering the course of the disease, it is intriguing to assume that dysregulation of osteoclast-macrophage lineage may have induced increased neopterin levels, increased cytokine levels, osteolytic process, and possibly FGF23 overproduction.

Upper spine morphology in hypophosphatemic rickets and healthy controls: a radiographic study.

BACKGROUND/OBJECTIVES: The aim of this study was to describe upper spine morphology in adult patients with hypophosphatemic rickets (HR) compared with controls to assess differences in spine morphology in terms of severity of skeletal impact and to study associations between spine morphology and craniofacial morphology. MATERIAL/METHODS: The study population comprised 36 HR patients and 49 controls. The atlas and axis dimensions were measured on cephalograms, and the differences between the groups were estimated by regression analysis. The upper spine morphology was visually assessed to estimate the prevalence of cervical vertebral anomalies. RESULTS: The dimensions of the atlas and the axis were larger in HR patients than in controls (P ≤ 0.001), and fusions (FUS) occurred more often in HR patients (39%) than in controls (6%; P ≤ 0.001). In HR patients, the length of the atlas correlated positively (P = 0.008) and the height of the dens correlated negatively (P = 0.043) with the severity of skeletal impact. The height of the posterior arch of the atlas and the length of the axis correlated negatively with the cranial base angle (P ≤ 0.017), and the vertical dimensions of the atlas correlated positively with the thickness of the occipital skull (P ≤ 0.015). The length of the atlas correlated positively with mandibular prognathism (P = 0.042). FUS correlated positively with the frontal and parietal thickness (P = 0.034 and P = 0.003, respectively). CONCLUSIONS: The dimension of the atlas and the axis and the prevalence of the FUS were increased in HR patients compared with controls. Upper spine dimensions were associated with craniofacial dimensions, primarily in relation to the posterior cranial fossa.

Morphological characteristics of frontal sinus and nasal bone focusing on bone resorption and apposition in hypophosphatemic rickets.

OBJECTIVES: To characterize the size and the morphology of the frontal sinus (i.e., structure evolved by bone resorption) and the nasal bone (i.e., structure evolved by bone formation) in adults with hypophosphatemic rickets (HR) compared with controls. SETTING AND SAMPLE POPULATION: Thirty-six patients with HR (12 males and 24 females) aged 21-74 years were included. The control group comprised 49 healthy individuals (23 males and 26 females) aged 20-79 years. MATERIAL AND METHODS: Profile cephalograms were obtained and the following measurements were included: height and width of the frontal sinus; length, width, and area of the nasal bone. The morphology of the nasal bone was assessed. Linear regression analyses were used to compare HR patients with controls. RESULTS: In HR patients, the size of the frontal sinus was unaffected (p = 0.406 to p = 0.862). The proximal width of the nasal bone, and the ratio between the proximal width and the axial length of the nasal bone were increased in HR patients (p < 0.05). CONCLUSIONS: The size of the frontal sinus was unaffected, indicating a normal ability of bone resorption within the bone. The morphology of the nasal bone was abnormal indicating a disturbance in bone formation during growth. The disturbances in nasal bone modeling were mainly expressed in the proximal part supported by structures of cartilaginous origin.

Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets.

Fibroblast growth factor 23 (FGF23) is a circulating factor secreted by osteocytes that is essential for phosphate homeostasis. In kidney proximal tubular cells FGF23 inhibits phosphate reabsorption and leads to decreased synthesis and enhanced catabolism of 1,25-dihydroxyvitamin D3 (1,25[OH]2 D3 ). Excess levels of FGF23 cause renal phosphate wasting and suppression of circulating 1,25(OH)2 D3 levels and are associated with several hereditary hypophosphatemic disorders with skeletal abnormalities, including X-linked hypophosphatemic rickets (XLH) and autosomal recessive hypophosphatemic rickets (ARHR). Currently, therapeutic approaches to these diseases are limited to treatment with activated vitamin D analogues and phosphate supplementation, often merely resulting in partial correction of the skeletal aberrations. In this study, we evaluate the use of FGFR inhibitors for the treatment of FGF23-mediated hypophosphatemic disorders using NVP-BGJ398, a novel selective, pan-specific FGFR inhibitor currently in Phase I clinical trials for cancer therapy. In two different hypophosphatemic mouse models, Hyp and Dmp1-null mice, resembling the human diseases XLH and ARHR, we find that pharmacological inhibition of FGFRs efficiently abrogates aberrant FGF23 signaling and normalizes the hypophosphatemic and hypocalcemic conditions of these mice. Correspondingly, long-term FGFR inhibition in Hyp mice leads to enhanced bone growth, increased mineralization, and reorganization of the disturbed growth plate structure. We therefore propose NVP-BGJ398 treatment as a novel approach for the therapy of FGF23-mediated hypophosphatemic diseases.