Oncogenic Hypophosphatemic Osteomalacia Research Articles

The case of oncogenic hypophosphatemic osteomalacia

Osteomalacia is a systemic bone disease, characterized by an excessive accumulation of non-mineralized osteoid and an imbalance in the organic matrix formation and mineralization. A rare cause of disease is tumor-induced osteomalacia, most often due to phosphaturic mesenchymal tumors (PMT). Usually there are benign small tumors, affecting the soft tissues and bones of any location. The basic pathogenesis of underlying oncogenic osteomalacia is a decreased renal tubular reabsorption of phosphate consequent to hyperproduction of fibroblast growth factor 23 in PMT. Clinical features are nonspecific, the average period from the symptoms onset to diagnosis reaches 3 years and at least 5 years before surgical treatment. Finding the tumour is crucial, as complete removal is curative. We present a clinical case of tumor-induced osteomalacia due to PMT required the complex differential diagnosis with other rare diseases.

Une fracture pathologique de la hanche chez un adulte révélant une ostéomalacie hypophosphorémique oncogénique secondaire à une dysplasie fibreuse des os.

Oncogenic hypophosphatemic osteomalacia is a rare acquired condition (about 160 reported cases). The initial abnormality is the unregulated secretion of FGF-23 by small growth mesenchymal tumors. Fibrous dysplasia is a well-known cause of oncogenic osteomalacia, with the polyostotic form complicated in 50% of cases with severe hypophosphatemia. We report here the case of a 43 years-old man, admitted for diffuses bone pain and muscular proximal weakness, evolving for 2 years, complicated with a pathological femoral neck fracture. Lab studies found severe hypophosphatemia and an elevation of alkaline phosphatases with normal levels of serum calcium, 25OH-vit D3 and PTH. X-Rays revealed a diffuse bone demineralization with multiple vertebral fractures and a fracture of the femoral neck associated with multiple lytic lesions of the femoral diaphysis. Histological examination has concluded fibrous dysplasia. Main etiologies, such as iatrogenic causes and Fanconi syndrome, have not been considered. Treatment with phosphorus associated with 1,25OH-Vit D3 has been installed, associated with intravenous infusions of bisphosphonates.

Resolution of Severe Oncogenic Hypophosphatemic Osteomalacia after Resection of a Deeply Located Soft-Tissue Tumour

Oncogenic osteomalacia is a rare metabolic bone disease characterized by phosphate leakage from the kidney and subsequent hypophosphatemia. It is caused by a phosphaturic factor produced by certain tumours. Removal of such tumours can completely cure the condition. Here, we report the case of a patient who was crippled with oncogenic osteomalacia. Extensive study revealed a tumour deeply located in the pelvis; removal of the tumour resulted in complete recovery. The tumour was identified as a mesenchymal tumour (mixed connective-tissue variant). The diagnostic evaluation, differential diagnosis, and treatment are discussed.

Recombinant MEPE can increase hydroxyapatite in vitro

The matrix extracellular phosphoglycoprotein (MEPE) gene is highly expressed in tumors that cause oncogenic hypophosphatemic osteomalacia (OHO). MEPE is also known as one of the bone-tooth matrix proteins and is associated with bone and teeth mineralization. We developed a rabbit polyclonal antibody directed against recombinant human MEPE after cloning its cDNA from the cDNA library of a human brain cDNA library. Using this antibody, we analyzed the distribution of MEPE in dog dental germ tissue by immunohistochemistry. In these specimens, MEPE was predominantly expressed by odontoblast cells and predentin, but not by dental pulp cells. Furthermore we used a steady-state agarose gel system, and the results suggested that MEPE could induce hydroxyapatite (HA). We propose that this protein has a potential effect on dental rehabilitation. Key words: MEPE, hydroxyapatite, steady-state agarose gel system.

Oncogenic hypophosphataemic osteomalacia: biomarker roles of fibroblast growth factor 23, 1,25-dihydroxyvitamin D3 and lymphatic vessel endothelial hyaluronan receptor 1

Oncogenic osteomalacia (OOM) is characterised by tumour production of fibroblast growth factor 23 (FGF23) that results in hypophosphataemia and renal phosphate wasting, reduced 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) synthesis and osteomalacia. Here, we demonstrate the roles of serum FGF23 and 1,25(OH)2D3, together with the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), as biomarkers for OOM. A previously well 52-year-old man presented with a 2-year history of generalised musculoskeletal pain and proximal myopathy. He had hypophosphataemia, elevated serum alkaline phosphatase activity, low serum 1,25(OH)2D3 and a reduced tubular maximum of phosphate/glomerular filtration rate. These findings indicated a diagnosis of OOM, but magnetic resonance imaging (MRI) and octreotide scintigraphy did not identify any tumours. Treatment with oral phosphate and calcitriol resolved the symptoms and biochemical abnormalities within 6 months. Four years later, he relapsed whilst on treatment with oral phosphate and calcitriol. Serum FGF23 concentration was elevated and MRI identified a 2 cm tumour within Hoffa's fat pad of the left knee. Removal of the tumour resulted in a complete resolution of symptoms and normalisation of the serum biochemical abnormalities including serum FGF23. Histology demonstrated a phosphaturic mesenchymal tumour, mixed connective tissue variant (PMTMCT), which revealed immunostaining with anti-LYVE-1 antibody and hence the presence of lymphatic vessels. Serum FGF23 and 1,25(OH)2D3 were found to be reliable biomarkers for OOM. In addition, the demonstration of lymphatics in the PMTMCT helps to distinguish this tumour from most typical benign haemangiomas.

P10 Oncogenic hypophosphatemic osteomalacia (OHO): report of two cases and review of literature

P10 Oncogenic hypophosphatemic osteomalacia (OHO): report of two cases and review of literature

The wrickkened pathways of FGF23, MEPE and PHEX.

The last 350 years since the publication of the first medical monograph on rickets (old English term wrickken) (Glisson et al., 1651) have seen spectacular advances in our understanding of mineral-homeostasis. Seminal and exciting discoveries have revealed the roles of PTH, vitamin D, and calcitonin in regulating calcium and phosphate, and maintaining healthy teeth and skeleton. However, it is clear that the PTH/Vitamin D axis does not account for the entire picture, and a new bone-renal metabolic milieu has emerged, implicating a novel set of matrix proteins, hormones, and Zn-metallopeptidases. The primary defects in X-linked hypophosphatemic rickets (HYP) and autosomal-dominant hypophosphatemic rickets (ADHR) are now identified as inactivating mutations in a Zn-metalloendopeptidase (PHEX) and activating mutations in fibroblast-growth-factor-23 (FGF23), respectively. In oncogenic hypophosphatemic osteomalacia (OHO), several tumor-expressed proteins (MEPE, FGF23, and FRP-4) have emerged as candidate mediators of the bone-renal pathophysiology. This has stimulated the proposal of a global model that takes into account the remarkable similarities between the inherited diseases (HYP and ADHR) and the tumor-acquired disease OHO. In HYP, loss of PHEX function is proposed to result in an increase in uncleaved full-length FGF23 and/or inappropriate processing of MEPE. In ADHR, a mutation in FGF23 results in resistance to proteolysis by PHEX or other proteases and an increase in half-life of full-length phosphaturic FGF23. In OHO, over-expression of FGF23 and/or MEPE is proposed to result in abnormal renal-phosphate handling and mineralization. Although this model is attractive, many questions remain unanswered, suggesting a more complex picture. The following review will present a global hypothesis that attempts to explain the experimental and clinical observations in HYP, ADHR, and OHO, plus diverse mouse models that include the MEPE null mutant, HYP-PHEX transgenic mouse, and MEPE-PHEX double-null-mutant.

Serum levels of matrix extracellular phosphoglycoprotein (MEPE) in normal humans correlate with serum phosphorus, parathyroid hormone and bone mineral density.

Matrix extracellular phosphoglycoprotein (MEPE), a member of the Small Integrin Binding Ligand N-linked Glycoprotein (SIBLING) family, is primarily expressed in normal bone and has been proposed as a phosphaturic factor because of high expression and secretion in oncogenic hypophosphatemic osteomalacia tumors. In order to begin to address the role of MEPE in normal human physiology, we developed a competitive ELISA to measure serum levels of MEPE. The ELISA was used to characterize the distribution pattern in a population consisting of 114 normal adult subjects. The mean value of MEPE was 476 +/- 247 ng/ml and levels decreased significantly with increasing age. MEPE levels were also significantly correlated with serum phosphorus and parathyroid hormone (PTH). In addition, MEPE levels correlated significantly with measures of bone mineral density in the femoral neck and total hip in a subset of 50 elderly subjects. The results are consistent with MEPE being involved in phosphate and bone metabolism in a normal population.

Matrix extracellular phosphoglycoprotein (MEPE) is highly expressed in osteocytes in human bone.

The matrix extracellular phosphoglycoprotein (MEPE) gene is highly expressed in tumors that cause oncogenic hypophosphatemic osteomalacia (OHO). MEPE is also known as one of the bone-tooth matrix proteins and is associated with bone mineralization. We developed a rabbit polyclonal antibody directed against recombinant human MEPE (rhMEPE) after cloning its cDNA from the cDNA library of a nasal tumor tissue causing OHO. Using this antibody, we analyzed the distribution of MEPE in human bones by immunohistochemistry. In bone specimens from normal subjects, MEPE was predominantly expressed by osteocytes and not by osteoblasts. In bone specimens from patients with osteomalacia, however, MEPE was focally expressed by deeply located osteocytes. We also compared the MEPE positivity of osteocytes in mineralized bone and non-mineralized osteoid obtained from patients with osteomalacia and osteoporosis. Among osteomalacia patients, MEPE positivity was seen in 87.5 +/- 8.6% of the osteocytes from mineralized bone compared with 7.8 +/- 6.4% of those from osteoid. Among osteoporosis patients, MEPE positivity was found in 95.3 +/- 0.5% of the osteocytes from mineralized bone compared with 4.9 +/- 5.7% of those from osteoid. MEPE was mainly expressed by osteocytes embedded in the matrix of mineralized bone from patients with osteomalacia or osteoporosis. Our data provide the first histological evidence that MEPE is predominantly expressed by osteocytes in human bone, with significant expression by osteocytes within mineralized bone.

Resolution of severe, adolescent-onset hypophosphatemic rickets following resection of an FGF-23-producing tumour of the distal ulna

Oncogenic hypophosphatemic osteomalacia (OHO) is an uncommon hypophosphatemic syndrome characterized by bone pain, proximal muscle weakness and rickets. It has been postulated that OHO results from overproduction of a humoral phosphaturic factor by an occult tumour. Recently, some OHO tumours have been shown to elaborate fibroblast growth factor-23 (FGF-23), which causes renal phosphate wasting when administered to mice. The purpose of this study was to undertake detailed investigations to confirm the diagnosis of OHO in a pediatric patient and to document the biochemical, radiographic and bone histological phenotype before and after tumour removal. We describe an 11-year-old, previously healthy girl with significant pain and functional disability associated with hypophosphatemic rickets. Circulating 1,25-(OH) 2 vitamin D was very low (14 pM; N: 40–140) while the FGF-23 serum level was markedly elevated [359.5 reference units (RU)/ml, N: 33–105]. An iliac bone biopsy revealed severe osteomalacia, but periosteocytic lesions, as are typical for X-linked hypophosphatemic rickets, were not seen. Sequence analyses of the PHEX and FGF23 genes were normal. A radiographic skeletal survey revealed a small exostosis of the left, distal ulnar metaphysis. A tumour was subsequently removed from this site and the pathology was consistent with benign, fibro-osseous tissue. Serum FGF-23 was normal when measured at 7 h post-operatively, while serum phosphate reached the low-normal range at 16 days following surgery. An iliac bone biopsy taken 5 months after the operation showed improvement, but not yet resolution, of the osteomalacia. Biochemical parameters of bone and mineral metabolism suggested that complete resolution of the osteomalacia was not achieved until 12 months following surgery. One year after tumour removal, the patient was pain-free and had resumed a normal level of activity. The rapid normalization of FGF-23 levels following removal of a benign tumour and the subsequent improvement in the biochemical and histological parameters of bone and mineral metabolism suggest that FGF-23 played a key role in this girl's disease.

A synthetic peptide fragment of human MEPE stimulates new bone formation in vitro and in vivo.

Matrix extracellular phosphoglycoprotein (MEPE) was proposed as a candidate for the phosphaturic hormone phosphatonin. We found that a synthetic peptide fragment of MEPE containing the RGD and SGDG sequence stimulated new bone formation in vitro and in vivo. Matrix extracellular phosphoglycoprotein (MEPE) was recently identified as a candidate for the phosphaturic hormone phosphatonin, which has been implicated in disturbed phosphate metabolism, rickets, and osteomalacia associated with X-linked hypophosphatemic rickets (XLH) and oncogenic hypophosphatemic osteomalacia (OHO). MEPE expression was predominantly found in osteoblasts, and mice deficient in a homolog of MEPE showed increased bone density, suggesting that MEPE produced in osteoblasts negatively regulates bone formation. In this study, we examined the effects of a synthetic 23mer peptide fragment of MEPE (AC-100, region 242-264) containing the RGD (integrin-binding) and SGDG (glycosaminoglycan-attachment) motif on bone formation in vitro and in vivo. The osteogenic activity of AC-100 was examined in organ cultures of neonatal mouse calvariae and in vivo by injecting AC-100 onto the calvariae of mice. Histomorphometric examination showed that AC-100 stimulated new bone formation with increased numbers of osteoblasts in neonatal mouse calvariae in organ culture. In contrast, synthetic MEPE fragment peptides without either the RGD or SGDG motif failed to increase new bone formation. Repeated daily subcutaneous injections of AC-100 onto the calvariae in mice increased bone thickness and stimulated new bone formation as determined by the calcein double-labeling technique. However, peptides in which the RGD or SGDG sequence was scrambled did not stimulate new bone formation in vivo. AC-100 increased cell proliferation and alkaline phosphatase activity and activated focal adhesion kinase (FAK) and extracellular signal-regulated protein kinase (ERK) in human primary osteoblasts. Our results show that a synthetic peptide corresponding with the sequence of human MEPE fragment stimulates new bone formation with increased number of osteoblasts. The results also suggest that the RGD and SGDG motifs are critical to the osteogenic activity of AC-100, presumably through activating integrin signaling pathways in osteoblasts. The anabolic effects of AC-100 may be beneficial for bone diseases associated with decreased bone formation.

Regulation of mRNA expression of matrix extracellular phosphoglycoprotein (MEPE)/ osteoblast/osteocyte factor 45 (OF45) by fibroblast growth factor 2 in cultures of rat bone marrow-derived osteoblastic cells.

Matrix extracellular phosphoglycoprotein (MEPE)/ osteoblast/osteocyte factor 45 (OF45) is a recently isolated RGD-containing matrix protein that acts as the tumor-derived phosphaturic factor in oncogenic hypophosphatemic osteomalacia. It is also highly expressed by osteoblasts and osteocytes. We examined the regulation of MEPE/OF45 mRNA expression in osteoblastic cells derived from high-density cultures of primary rat bone marrow stromal cells incubated with dexamethasone, beta-glycerophosphate, and ascorbic acid. The level of MEPE/OF45 mRNA in these cells was down-regulated by the addition of fibroblast growth factor 2 (FGF2) for 48 h. These effects were observed in a dose-dependent manner between 2 and 10 ng/mL. FGF2 also reduced the expression of osteocalcin mRNA in these cells. In contrast, bone sialoprotein mRNA expression was increased by FGF2, while alpha1(I) procollagen mRNA expression was not altered. Additionally, neither Runx2 and osterix mRNA expression nor cell proliferation were affected by the addition of FGF2 in these high-density cultures, indicating that regulation by FGF2 may not be dependent on these transcription factors or on the proliferation of cells. Experiments using actinomycin D indicated that FGF2 decreased the stability of the MEPE/OF45 mRNA. Moreover, inhibition of a specific mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) by PD98059 blocked FGF2-regulated MEPE/OF45 expressions, indicating that this regulation requires the MAPK pathway. These results suggest that MEPE/OF45 gene is one of the targets of FGF2 and may play an important role during bone formation and calcification.

Oncogenic Hypophosphatemic Osteomalacia Associated With a Nasal Hemangiopericytoma

We report a patient with a nasal hemangiopericytoma associated with an oncogenic hypophosphatemic osteomalacia (OHO). This syndrome results from tumor products that decrease renal tubular phosphate resorption, leading to the osteomalacia. This patient presented with classic bone manifestations of osteomalacia and a nasal tumor. Laboratory studies performed before the first resection of the tumor included normal serum calcium, hypophosphatemia due to decreased tubular reabsorption of phosphate, and an undetectable serum 1,25 dihydroxy vitamin D level. Serum parathormone level was normal. Anterior iliac crest bone biopsy showed characteristic signs of osteomalacia that included increased osteoid and delayed mineralization. A partial resection of the nasal tumor was performed. After the first surgery the patient showed detectable serum level of 1,25 dihydroxy vitamin D, and transient normalization of the tubular reabsorption of phosphate. The patient was also treated with phosphate supplements and vitamin D with transient control of her clinical manifestations and improvement of the radiographic signs of osteomalacia. Three months after surgery, the serum level of 1,25 dihydroxy vitamin D level again became undetectable. After selective embolization of the tumor, followed by an apparent complete tumor resection and postoperative radiation therapy, her hypophosphatemia and decreased phosphate tubular reabsorption persisted. Therefore, biochemical changes associated with hemangiopericytoma induced OHO may persist even after apparent total tumor resection. Clinicians should be aware of the oncogenic basis for some osteomalacia, as seen in this patient.

MEPE has the properties of an osteoblastic phosphatonin and minhibin

Matrix extracellular phosphoglycoprotein (MEPE) is expressed exclusively in osteoblasts, osteocytes and odontoblasts with markedly elevated expression found in X-linked hypophosphatemic rickets (Hyp) osteoblasts and in oncogenic hypophosphatemic osteomalacia (OHO) tumors. Because these syndromes are associated with abnormalities in mineralization and renal phosphate excretion, we examined the effects of insect-expressed full-length human-MEPE (Hu-MEPE) on serum and urinary phosphate in vivo, 33PO 4 uptake in renal proximal tubule cultures and mineralization of osteoblast cultures. Dose-dependent hypophosphatemia and hyperphosphaturia occurred in mice following intraperitoneal (IP) administration of Hu-MEPE (up to 400 μg kg −1 31 h −1), similar to mice given the phosphaturic hormone PTH (80 μg kg −1 31 h −1). Also the fractional excretion of phosphate (FEP) was stimulated by MEPE [65.0% ( P < 0.001)] and PTH groups [53.3% ( P < 0.001)] relative to the vehicle group [28.7% (SEM 3.97)]. In addition, Hu-MEPE significantly inhibited 33PO 4 uptake in primary human proximal tubule renal cells (RPTEC) and a human renal cell line (Hu-CL8) in vitro ( V max 53.4% inhibition; K m 27.4 ng/ml, and V max 9.1% inhibition; K m 23.8 ng/ml, respectively). Moreover, Hu-MEPE dose dependently (50–800 ng/ml) inhibited BMP2-mediated mineralization of a murine osteoblast cell line (2T3) in vitro. Inhibition of mineralization was localized to a small (2 kDa) cathepsin B released carboxy-terminal MEPE peptide (protease-resistant) containing the acidic serine–aspartate-rich motif (ASARM peptide). We conclude that MEPE promotes renal phosphate excretion and modulates mineralization.

Immunohistochemical detection of FGF-23 protein in tumors that cause oncogenic osteomalacia.

Oncogenic hypophosphatemic osteomalacia (OOM) is a rare disease characterized by hypophosphatemia, inappropriately low levels of circulating 1,25-dihydroxyvitamin D(3) and osteomalacia. The disease is most commonly caused by benign mesenchymal tumors that produce, among several other factors, fibroblast growth factor-23 (FGF-23). Current evidence thus suggests that this protein has an important role in the regulation of phosphate homeostasis. By producing polyclonal antibodies against human FGF-23 protein we wanted to determine the localization of FGF-23 protein in OOM tumors that express FGF-23 mRNA. Three polyclonal antibodies were raised in rabbits against three different peptides with sequences derived from human FGF-23: [Cys-70]FGF-23(51-69)amide, [Tyr-223]FGF-23(206-222)amide and [Tyr-224]FGF-23(225-244)amide. One of the resulting antisera was subsequently used for immunohistochemistry on sections from five different tumors causing OOM. FGF-23 mRNA expression was confirmed with in situ hybridization. After affinity purification, two of three antisera detected recombinant human FGF-23 by Western blot analysis. Through immunohistochemical analysis using the anti-[Tyr-224]FGF-23(225-244)amide antibody and through in situ hybridization using full-length antisense FGF-23 cRNA as a probe, we showed that abundant amounts of FGF-23 protein and mRNA are present in certain tumor cells of five different OOM tumors. We conclude that OOM tumors express FGF-23 protein and that the immunohistochemical detection of FGF-23 in OOM tumors is feasible and may help in establishing the diagnosis of tumor-induced hypophosphatemia through analysis of biopsies or surgical specimens.

MEPE, the Gene Encoding a Tumor-Secreted Protein in Oncogenic Hypophosphatemic Osteomalacia, Is Expressed in Bone

The MEPE (matrix extracellular phosphoglycoprotein) gene is a strong candidate for the tumor-derived phosphaturic factor in oncogenic hypophosphatemic osteomalacia (OHO). X-linked hypophosphatemia (XLH) is phenotypically similar to OHO and results from mutations in PHEX, a putative metallopeptidase believed to process a factor(s) regulating bone mineralization and renal phosphate reabsorption. Here we report the isolation of the murine homologue of MEPE, from a bone cDNA library, that encodes a protein of 433 amino acids, 92 amino acids shorter than human MEPE. Mepe, like Phex, is expressed by fully differentiated osteoblasts and down-regulated by 1,25-(OH)2D3. In contrast to Phex, Mepe expression is markedly increased during osteoblast-mediated matrix mineralization. Greater than normal Mepe mRNA levels were observed in bone and osteoblasts derived from Hyp mice, the murine homologue of human XLH. Our data provide the first evidence that MEPE/Mepe is expressedby osteoblasts in association with mineralization.

The Autosomal Dominant Hypophosphatemic Rickets (ADHR) Gene Is a Secreted Polypeptide Overexpressed by Tumors that Cause Phosphate Wasting

The gene mutated in autosomal dominant hypophosphatemic rickets (ADHR), a phosphate wasting disorder, has been identified as FGF-23, a protein that shares sequence homology with fibroblast growth factors (FGFs). Patients with ADHR display many of the clinical and laboratory characteristics that are observed in patients with oncogenic hypophosphatemic osteomalacia (OHO), a disorder thought to arise by the secretion of a phosphate wasting factor from different mesenchymal tumors. In the present studies, we therefore investigated whether FGF-23 is a secreted factor and whether it is abundantly expressed in OHO tumors. After transient transfection of OK-E, COS-7, and HEK293 cells with the plasmid encoding full-length FGF-23, all three cell lines efficiently secreted two protein species into the medium that were approximately 32 and 12 kDa upon SDS-PAGE and subsequent Western blot analysis using an affinity-purified polyclonal antibody to FGF-23. Furthermore, Northern blot analysis using total RNA from five different OHO tumors revealed extremely high levels of FGF-23 mRNA, and Western blot analysis of extracts from a sixth tumor detected the 32 kDa FGF-23 protein species. In summary, FGF-23, the gene mutated in ADHR, is a secreted protein and its mRNA is abundantly expressed by several different OHO tumors. Our findings indicate that FGF-23 may be a candidate phosphate wasting factor, previously designated "phosphatonin".

MEPE, a New Gene Expressed in Bone Marrow and Tumors Causing Osteomalacia

Oncogenic hypophosphatemic osteomalacia (OHO) is characterized by a renal phosphate leak, hypophosphatemia, low-serum calcitriol (1,25-vitamin-D3), and abnormalities in skeletal mineralization. Resection of OHO tumors results in remission of the symptoms, and there is evidence that a circulating phosphaturic factor plays a role in the bone disease. This paper describes the characterization and cloning of a gene that is a candidate for the tumor-secreted phosphaturic factor. This new gene has been named MEPE (matrix extracellular phosphoglycoprotein) and has major similarities to a group of bone–tooth mineral matrix phospho-glycoproteins (osteopontin (OPN; HGMW-approved symbol SPP1), dentin sialo phosphoprotein (DSPP), dentin matrix protein 1 (DMP1), bone sialoprotein II (IBSP), and bone morphogenetic proteins (BMP). All the proteins including MEPE contain RGD sequence motifs that are proposed to be essential for integrin–receptor interactions. Of further interest is the finding that MEPE, OPN, DSPP, DMP1, IBSP, and BMP3 all map to a defined region in chromosome 4q. Refined mapping localizes MEPE to 4q21.1 between ESTs D4S2785 (WI-6336) and D4S2844 (WI-3770). MEPE is 525 residues in length with a short N-terminal signal peptide. High-level expression of MEPE mRNA occurred in all four OHO tumors screened. Three of 11 non-OHO tumors screened contained trace levels of MEPE expression (detected only after RT-PCR and Southern 32P analysis). Normal tissue expression was found in bone marrow and brain with very-low-level expression found in lung, kidney, and human placenta. Evidence is also presented for the tumor secretion of clusterin (HGMW-approved symbol CLU) and its possible role as a cytotoxic factor in one of the OHO patients described.

Molecular and cellular regulation of renal phosphate transporters in X-linked hypophosphatemia

Recent investigations of X-linked hypophosphatemia support the concept that the kidney is intrinsically normal in this disorder, and that the characteristic phosphaturia is caused by a humoral factor. The mechanisms involved in the pathophysiology of X-linked hypophosphatemia, Hyp, and oncogenic hypophosphatemic osteomalacia are complex and are the results of mutations in a putative zinc metalloprotease. Inactivation inPHEX gene function initiates a series of events that result in severe perturbations in renal Pi transport and metabolism of vitamin D. There are a number of possible working models that could explain the experimental observations. However, our studies clearly show that a humoral factor (phosphatonin) inhibits the transcription of the type II Na+/Pi cotransporter gene (Fig. 4). Phosphatonin may be a key modulator of phosphate homeostasis.

X-linked rickets and tumor-acquired osteomalacia:PHEX and the missing link

Dietary rickets has been recognized as a major cause of skeletal abnormalities in the industrialized world for more than 350 years. In recent times, familial and tumor forms of rickets were found to be resistant to vitamin D3 supplementation and light. The main nondietary types of rickets and osteomalacia include: a) X-linked vitamin D-resistant, hypophosphatemic rickets; b) hereditary hypercalciuria with hypophosphatemic rickets; c) Dent's disease including certain types of renal Fanconi syndrome; d) renal 1α-hydroxylase deficiency; e) defects in the 1,25-dihydroxy vitamin D3 receptor (end-organ resistance); f) autosomal dominant forms of rickets; and g) oncogenic hypophosphatemic osteomalacia. This review will describe the recent advances in our knowledge of the molecular defects in hypophosphatemic rickets and tumor-acquired osteomalacia.