Original Article
Brief Report
Inhibition of Renal Phosphate Transport by a Tumor Product in a Patient with Oncogenic Osteomalacia
N Engl J Med 1994; 330:1645-1649June 9, 1994
- Article
In tumor-induced osteomalacia, a rare syndrome characterized by hypophosphatemia, hyperphosphaturia, low plasma 1,25-dihydroxyvitamin D concentrations, and osteomalacia,1-5 all biochemical and pathological abnormalities disappear when the tumor is removed. Tumors associated with this syndrome are thought to secrete a substance that inhibits the renal tubular reabsorption of phosphate,1-5 but whether this factor interacts directly with renal tubular cells is not known. We investigated the ability of medium in which sclerosing hemangioma cells from a patient with oncogenic osteomalacia were cultured to alter sodium-dependent phosphate transport in opossum-kidney epithelial cells. We found that the medium inhibited phosphate transport, without increasing cellular concentrations of cyclic adenosine monophosphate (cAMP). The medium had parathyroid hormone (PTH)-like immunoreactivity but no PTH-related protein immunoreactivity, and its action was not blocked by a PTH antagonist.
Case Report
The patient was first seen at the Mayo Clinic in November 1974, at the age of 47 years, with a seven-year history of aching that progressed through her arms and legs. She was the product of a normal pregnancy, and her growth and development had been normal. Physical examination revealed moderate proximal-muscle weakness. A movable, nontender mass measuring 2 by 1.5 cm was identified in the soft tissue of the distal anterior thigh. The serum calcium concentration was normal, the phosphate concentration was low, and the alkaline phosphatase concentration was high (Table 1Table 1
Serum, Plasma, and Urinary Biochemical Values in a Patient with Oncogenic Osteomalacia.). An iliac-bone biopsy done after double tetracycline labeling revealed osteomalacia. The patient was not treated with phosphate or vitamin D.The patient had a spontaneous fracture of her left proximal femur in September 1975. At that time, the subcutaneous mass in the distal thigh, which had enlarged, was excised. Histologic examination revealed a sclerosing hemangioma. The patient's fracture healed, her weakness improved, and her serum phosphate concentration increased to normal. She was well for the next 16 years. In October 1991, she began to have vague lower-extremity pain and noticed a mass at the site from which the hemangioma had been excised. Serum total and ionized calcium concentrations were normal, the phosphate concentration was low, and the alkaline phosphatase concentration was high (Table 1). The plasma concentration of 25-hydroxyvitamin D was normal and the concentration of 1,25-dihydroxyvitamin D was at the lower limit of the normal range6. Serum concentrations of sodium, potassium, glucose, total protein, aspartate aminotransferase, bilirubin, uric acid, creatinine, and albumin were normal. Urinalysis revealed osmolality of 489 mOsm per kilogram, with a pH of 5.3, a glucose concentration of 29 mg per deciliter, and no abnormal findings on microscopy. The pH of venous blood was 7.39.
By December 1992 the patient's movements and gait had become cautious, and she used her arms to rise from a sitting position. A firm, movable mass measuring 2 cm in diameter was present in the soft tissue of the distal anterior thigh beneath the healed surgical scar. Radiographic examination demonstrated degenerative arthritis of both hips and anterior compression of the T6 and T7 vertebral bodies. The serum or plasma concentrations of phosphate, calcium, 1,25-dihydroxyvitamin D, and osteocalcin7 were low (Table 1), as was the maximal capacity of the renal tubules to reabsorb phosphorus divided by the glomerular filtration rate8. Serum or plasma concentrations of PTH,9 PTH-related protein,10 25-hydroxyvitamin D, and alkaline phosphatase were normal. A transiliac-bone biopsy, performed after double tetracycline labeling, showed a mineralization defect (osteomalacia) (Figure 1AFigure 1
Histologic Sections of Bone and Tumor Tissue from a Patient with Oncogenic Osteomalacia. and Figure 1B)11.The soft-tissue mass was excised in January 1993; pathological examination again revealed a sclerosing hemangioma (Figure 1C). Postoperatively, when the patient was asymptomatic, her serum phosphate and plasma 1,25-dihydroxyvitamin D concentrations were normal, but the serum osteocalcin concentration was elevated (Table 1).Methods
Serum, plasma, and urinary constituents were measured by standard techniques in the Mayo Medical Laboratories.
Cell Culture
For the tumor-cell culture, 1.5 g of the tumor tissue removed in 1993 was dissociated enzymatically in phosphate-buffered saline containing 0.8 percent collagenase, 0.25 percent trypsin, and 0.02 mg of DNAase per milliliter. The cells were washed once in RPMI medium and resuspended in 30 ml of RPMI medium containing 10 percent calf bovine serum. The cells were plated into three tissue-culture dishes at a concentration of 1.3 × 105 cells per milliliter and cultured at 37 °C in a humidified atmosphere of 95 percent air and 5 percent carbon dioxide. The cells grew slowly in vitro. Conditioned medium was removed on days 2 and 8, pooled, and stored at -70 °C.
Opossum-kidney cells (a gift of Dr. Leonard Forte, University of Missouri) were cultured in 45 percent Dulbecco's modified Eagle's medium and 45 percent F12 medium, with 10 percent fetal-calf serum, 100 U of penicillin per milliliter, and 100 μg of streptomycin per milliliter. The cells then were seeded at a density of about 1 × 105 per well in 24-well tissue-culture plates. Assays were carried out two to three days after the cells were confluent.
Measurement of Sodium-Dependent Phosphate, Alanine, and Glucose Cotransport
The method used to measure sodium-dependent phosphate, alanine, and glucose cotransport has been described in detail elsewhere12,13. In brief, 100 microliters of growth medium obtained from the tumor-cell cultures on day 2, 100 microliters of RPMI medium with 10 percent fetal-calf serum, bovine PTH 1-34 (6 × 10-9 M), or PTH vehicle was added to the opossum-kidney cells to assess their effect on sodium-dependent phosphate transport. [Nle8, Nle18, Tyr34] bovine PTH (3-34) amide (10-5 M) was used as a PTH antagonist.
For the measurement of sodium-dependent phosphate transport, 0.1 mM dibasic potassium phosphate was included in the transport medium and [32P]dibasic potassium phosphate was added to a final specific activity of 2 micro Ci per milliliter. For sodium-dependent alanine transport, 0.1 mM l-alanine and [3H]l-alanine were added (final specific activity, 1 micro Ci per milliliter). For glucose transport, 0.1 mM methyl-α-glucopyranoside and methyl(alpha-d-[u-14C] gluco) pyranoside were added (final specific activity, 0.2 micro Ci per milliliter). The transport of phosphate, alanine, and methyl-alpha-glucopyranoside was assayed separately. Each transport reaction was measured in three or four duplicate wells. Each assay included three or four blank wells to correct for solute bound to the surfaces of the cells and the well and in intercellular spaces.
Treatment of Medium Obtained from Tumor-Cell Cultures
Medium (0.5 ml) obtained on day 2 of tumor-cell culture and control medium were boiled for 10 minutes in a water bath. Medium (0.5 ml) harvested from the tumor-cell cultures was dialyzed against water at 4 °C overnight with membranes that retained particles with a molecular weight of either 8 kd or larger or 25 kd or larger. The effect of the boiled or dialyzed medium on phosphate transport in opossum-kidney cells was measured.
Assays
Enzyme immunoassay was used to measure cAMP14. PTH-like substances were sought in medium obtained from tumor-cell cultures on day 2 with an immunochemiluminometric midregion assay9. This assay measures intact PTH and N-terminal PTH fragments but not C-terminal PTH (53-84). RPMI medium containing either 10 percent fetal-calf serum or 10 percent fetal-calf serum conditioned by the growth of Chinese hamster-ovary cells was used as the control medium. PTH-related protein was measured by radioimmunoassay with antibodies against PTH-related protein10.
Tumor Implantation into Nude Mice
Small fragments of the excised tumor were implanted into five nude mice. Serum phosphate then was measured periodically in the mice.
Statistical Analysis
The results of the studies of solute uptake by opossum-kidney cells were analyzed by analysis of variance for a randomized block design (trays being blocks). An overall test for treatment effects in this analysis was therefore adjusted for differences between trays. Pairwise comparisons (tumor medium vs. vehicle and PTH vs. PTH vehicle) were done at an alpha level of 0.025 to adjust for two pairwise comparisons. The effect of dialysis was examined by comparing tumor medium with control medium before and after dialysis with membranes capable of retaining particles 8 kd or larger or particles 25 kd or larger, with a two-sample t-test at an alpha level of 0.017 (i.e., adjustment for three tests). All statistical tests were two-sided.
Results
Histologic and histomorphometric analysis of the transiliac-bone specimen obtained by biopsy in 1993 showed a mineralization defect (osteomalacia) (Figure 1A and Figure 1B). The tumor (Figure 1C) was a sclerosing hemangioma.
The effect of the medium obtained from tumor-cell cultures on sodium-dependent phosphate transport in opossum-kidney cells was compared with that of bovine PTH 1-34. Medium obtained on day 2 of tumor-cell culture significantly inhibited phosphate transport in cultured opossum-kidney cells (Figure 2Figure 2
Effect of Medium Obtained from Tumor-Cell Cultures on Solute Transport in Cultured Epithelial Opossum-Kidney Cells.), as did medium harvested from the tumor cells on day 8 (data not shown). Medium collected on or after day 15 did not inhibit phosphate transport. Medium obtained on day 2 did not significantly inhibit alanine and glucose transport (Figure 2).Boiling the medium obtained from tumor-cell cultures on day 2 for 10 minutes abolished the inhibition of phosphate transport in opossum-kidney cells. Medium dialyzed with a membrane capable of retaining particles 8 kd or larger inhibited sodium-dependent phosphate transport in opossum-kidney cells, whereas medium dialyzed with a membrane capable of retaining particles 25 kd or larger did not (Table 2Table 2
Effect of Dialysis on the Inhibitory Properties of Medium Obtained from Tumor-Cell Cultures on Phosphate Transport in Opossum-Kidney Cells.). [Nle8, Nle18, Tyr34] bovine PTH (3-34) amide did not block the phosphate-inhibiting effect of medium obtained from tumor-cell cultures in opossum-kidney cells.The effect of the medium obtained from tumor-cell cultures on the production of cAMP was compared with that of the bovine PTH 1-34. As shown in Figure 3Figure 3
Effect of Medium Obtained from Tumor-Cell Cultures on cAMP Accumulation in Cultured Epithelial Opossum-Kidney Cells., bovine PTH 1-34 increased the accumulation of cAMP in opossum-kidney cells, whereas medium from tumor-cell cultures did not.PTH-like immunoreactivity was twice as high in medium obtained from tumor-cell cultures on day 2 as in control RPMI medium or RPMI medium exposed to Chinese hamster-ovary cells (2.1 pmol per liter vs. 0.9 and 1.2 pmol per liter, respectively). When the medium from tumor-cell cultures was serially diluted with PTH-free serum, the resultant values differed from those that would have been obtained had authentic PTH or an N-terminal fragment of PTH been present in the sample (undiluted medium, 2.1 pmol per liter; 1:2 dilution, 0.4 pmol per liter; 1:4 dilution, 0.09 pmol per liter; and 1:8 dilution, 0.02 pmol per liter). PTH-related protein was not detectable in the medium obtained from tumor-cell cultures or in the patient's serum.
The mean (±SE) serum phosphate concentrations in the five nude mice 6, 9, and 10 months after the implantation of tumor fragments were 8.4 ±0.2 mg per deciliter (2.7 ±0.1 mmol per liter), 4.7 ±0.9 mg per deciliter (1.5 ±0.3 mmol per liter), and 5.4 ±0.2 mg per deciliter (1.5 ±0.1 mmol per liter), respectively. The corresponding values in two control nude mice were 9.3 ±2.4 mg per deciliter (3.0 ±0.7 mmol per liter), 6.2 ±0.6 mg per deciliter (2.0 ±0.2 mmol per liter), and 7.2 ±0.1 mg per deciliter (2.3 ±0.05 mmol per liter).
Discussion
Decreased renal phosphate transport is a rare cause of metabolic bone disease; such a defect occurs in Fanconi's syndrome, familial hypophosphatemia,1,2 and tumor-associated hypophosphatemia (oncogenic osteomalacia)15-19. Our patient had the typical manifestations of tumor-associated hypophosphatemia. Removal of the tumor was associated with reversal of the hypophosphatemia and all other metabolic abnormalities.
Cell-culture medium conditioned by the growth of tumor cells from the patient inhibited sodium-dependent phosphate transport in cultured renal cells. We did not measure sodium-independent phosphate transport because this contributes little (<6 percent) to total phosphate transport in the kidney under these experimental conditions12. The inhibitory effect was lost when the medium was boiled or was dialyzed against a membrane capable of filtering 25-kd particles. The inhibitory effect on phosphate transport in the cultured renal cells was independent of the accumulation of cAMP. We have no information regarding the nature of the second messenger (if any) that mediates the effect of the tumor factor on the kidney. The absence of an increase in cAMP in the renal cells after the addition of medium obtained from tumor-cell cultures argues against a role for PTH, PTH-related protein, or an N-terminal bioactive fragment of these hormones in the pathogenesis of hypophosphatemia. The absence of both hypercalcemia and increased serum PTH concentrations in the patient supports this contention. Furthermore, the finding that a PTH antagonist had no effect on the changes in phosphate transport in opossum-kidney cells induced by the medium from tumor-cell cultures suggests that the factor is not PTH itself.
Phosphaturia contributes to the pathogenesis of osteomalacia in patients with oncogenic osteomalacia. PTH or PTH-related peptide, well-known phosphaturic agents,20,21 cannot be the mediators of the phosphaturia because the patients have normal serum calcium and PTH concentrations. Urinary excretion of cAMP is not increased in patients with this syndrome, but it usually is increased in patients with hyperparathyroidism or cancer-associated hypercalcemia caused by PTH-related peptide. Serum phosphate concentrations in nude mice implanted with pieces of the tumor gradually decreased after implantation; however, the pattern of change in the control mice was similar. The clinical course of the patient after tumor removal is consistent with the presence of a circulating phosphaturic factor.
Plasma 1,25-dihydroxyvitamin D concentrations are low in patients with oncogenic osteomalacia, despite the presence of hypophosphatemia,21-23 which usually increases plasma 1,25-dihydroxyvitamin D concentrations by stimulating the renal 25-hydroxyvitamin D-1α-hydroxylase in a PTH-independent manner24. Deficient production of 1,25-dihydroxyvitamin D could be a factor contributing to the pathogenesis of oncogenic osteomalacia in these patients,4,25,26 because in some patients the clinical and biochemical abnormalities improve during calcitriol therapy1. In a recent study, 25-hydroxyvitamin D-1alpha-hydroxylase activity in cultured renal tubular cells was decreased by incubating the cells with tumor extracts; the extracts presumably contained a substance that inhibited the formation of 1,25-dihydroxyvitamin D26.
We have demonstrated that culture medium conditioned by the growth of sclerosing hemangioma cells obtained from a patient with oncogenic osteomalacia inhibited phosphate transport in renal epithelial cells. The factor elaborated by the tumor cells has a low molecular weight and is heat-sensitive.
Supported by grants (DK 25409, DK 42971, CA-37343, and RR 00585) from the National Institutes of Health.
Source Information
From the Nephrology Research Unit (Q.C., R.K.), the Neuroimmunology Research Laboratory (V.A.L.), the Section of Biostatistics (A.R.Z.), and the Departments of Medicine (S.F.H., R.K.), Neurology and Immunology (V.A.L.), and Laboratory Medicine and Pathology (P.C.K., G.G.K.), Mayo Clinic, Rochester, Minn.
Address reprint requests to Dr. Kumar at the Mayo Clinic, 200 First St., SW, 911A Guggenheim Bldg., Rochester, MN 55905.
- References
References
1
Lobaugh B, Burch WM Jr, Drezner MK. Abnormalities of vitamin D metabolism and action in the vitamin D resistant rachitic and osteomalacic diseases. In: Kumar R, ed. Vitamin D: basic and clinical aspects. Boston: Martinus Nijhoff, 1984:665-720.
2
Fanconi A ,Fischer JA ,Prader A . Serum parathyroid hormone concentrations in hypophosphataemic vitamin D resistant rickets. Helv Paediatr Acta 1974;29:187-194
Medline3
McCance RA . Osteomalacia with Looser's nodes (milkman's syndrome) due to a raised resistance to vitamin D acquired about the age of 15 years. Q J Med 1947;16:33-46
Web of Science | Medline4
Fukumoto Y ,Tarui S ,Tsukiyama K , et al. Tumor-induced vitamin D-resistant hypophosphatemic osteomalacia associated with proximal renal tubular dysfunction and 1,25-dihydroxyvitamin D deficiency. J Clin Endocrinol Metab 1979;49:873-878
CrossRef | Web of Science | Medline5
Weidner N ,Bar RS ,Weiss D ,Strottmann MP . Neoplastic pathology of oncogenic osteomalacia/rickets. Cancer 1985;55:1691-1705
CrossRef | Web of Science | Medline6
Kao PC ,Heser DW . Simultaneous determination of 25-hydroxy- and 1,25-dihydroxyvitamin D from a single sample by dual-cartridge extraction. Clin Chem 1984;30:56-61
Web of Science | Medline7
Kao PC ,Riggs BL ,Schryver PG . Development and evaluation of an osteocalcin chemiluminoimmunoassay. Clin Chem 1993;39:1369-1374
Web of Science | Medline8
Walton RJ ,Bijvoet OLM . Nomogram for derivation of renal threshold phosphate concentration. Lancet 1975;2:309-310
CrossRef | Web of Science | Medline9
Klee GG ,Preissner CM ,Schryver PG ,Taylor RL ,Kao PC . Multisite immunochemiluminometric assay for simultaneously measuring whole-molecule and amino-terminal fragments of human parathyrin. Clin Chem 1992;38:628-635
Web of Science | Medline10
Kao PC ,Klee GG ,Taylor RL ,Heath H III . Parathyroid hormone-related peptide in plasma of patients with hypercalcemia and malignant lesions. Mayo Clin Proc 1990;65:1399-1407
Web of Science | Medline11
Hodgson SF ,Johnson KA ,Muhs JM ,Lufkin EG ,McCarthy JT . Outpatient percutaneous biopsy of the iliac crest: methods, morbidity, and patient acceptance. Mayo Clin Proc 1986;61:28-33
Web of Science | Medline12
Al-Mahrouq HA ,Rassier ME ,Dousa TP ,Kempson SA . Sodium-dependent transport by cultured proximal tubule cells. J Tissue Cult Methods 1991;13:185-190
CrossRef13
Smith PK ,Krohn RI ,Hermanson GT , et al. Measurement of protein using bicinchoninic acid. Anal Biochem 1985;150:76-85[Erratum, Anal Biochem 1987;163:279.]
CrossRef | Web of Science | Medline14
Horton JK ,Martin RC ,Kalinka S , et al. Enzyme immunoassays for the estimation of adenosine 3',5' cyclic monophosphate and guanosine 3',5' cyclic monophosphate in biological fluids. J Immunol Methods 1992;155:31-40
CrossRef | Web of Science | Medline15
Harrison HE . Oncogenous rickets: possible elaboration by a tumor of a humoral substance inhibiting tubular reabsorption of phosphate. Pediatrics 1973;52:432-434
Web of Science | Medline16
Ryan EA ,Reiss E . Oncogenous osteomalacia: review of the world literature of 42 cases and report of two new cases. Am J Med 1984;77:501-512
CrossRef | Web of Science | Medline17
Popovtzer MM . Tumor-induced hypophosphatemic osteomalacia (TUO): evidence for a phosphaturic cyclic AMP-independent action of tumor extract. Clin Res 1981;29:418A-418A abstract.18
Aschinberg LC ,Solomon LM ,Zeis PM ,Justice P ,Rosenthal IM . Vitamin D-resistant rickets associated with epidermal nevus syndrome: demonstration of a phosphaturic substance in the dermal lesions. J Pediatr 1977;91:56-60
CrossRef | Web of Science | Medline19
Salassa RM ,Jowsey J ,Arnaud CD . Hypophosphatemic osteomalacia associated with “nonendocrine” tumors. N Engl J Med 1970;283:65-70
Full Text | Web of Science | Medline20
Caverzasio J ,Rizzoli R ,Bonjour JP . Sodium-dependent phosphate transport inhibited by parathyroid hormone and cyclic AMP stimulation in an opossum kidney cell line. J Biol Chem 1986;261:3233-3237
Web of Science | Medline21
Weidner N . Review and update: oncogenic osteomalacia-rickets. Ultrastruct Pathol 1991;15:317-333
CrossRef | Web of Science | Medline22
Sweet RA ,Males JL ,Hamstra AJ ,DeLuca HF . Vitamin D metabolite levels in oncogenic osteomalacia. Ann Intern Med 1980;93:279-280
Web of Science | Medline23
Drezner MK ,Feinglos MN . Osteomalacia due to 1α,α25-dihydroxycholecalciferol deficiency: association with a giant cell tumor of bone. J Clin Invest 1977;60:1046-1053
CrossRef | Web of Science | Medline24
Ribovich ML ,DeLuca HF . Effect of dietary calcium and phosphorus on intestinal calcium absorption and vitamin D metabolism. Arch Biochem Biophys 1978;188:145-156
CrossRef | Web of Science | Medline25
Drezner MK, Lobaugh B, Lyles KW, Carey DE, Paulson DF, Harrelson JM. The pathogenesis and treatment of tumor-induced osteomalacia. In: Norman AW, Schaefer K, eds. Vitamin D: chemical, biochemical, and clinical endocrinology of calcium metabolism. Berlin, Germany: Walter de Gruyter, 1982:949-54.
26
Miyauchi A ,Fukase M ,Tsutsumi M ,Fujita T . Hemangiopericytoma-induced osteomalacia: tumor transplantation in nude mice causes hypophosphatemia and tumor extracts inhibit renal 25-hydroxyvitamin D1-hydroxylase activity. J Clin Endocrinol Metab 1988;67:46-53
CrossRef | Web of Science | Medline
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CrossRef14
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CrossRef20
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CrossRef23
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CrossRef24
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CrossRef29
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CrossRef32
Carrie L. Heike, Michael L. Cunningham, Robert D. Steiner, Deborah Wenkert, Robin L. Hornung, Joseph S. Gruss, Francis H. Gannon, William H. McAlister, Steven Mumm, Michael P. Whyte. (2005) Skeletal changes in epidermal nevus syndrome: Does focal bone disease harbor clues concerning pathogenesis?. American Journal of Medical Genetics Part A 139A:2, 67-77
CrossRef33
Michael T Collins, John R Lindsay, Alka Jain, Marilyn H Kelly, Carolee M Cutler, Lee S Weinstein, Jie Liu, Neal S Fedarko, Karen K Winer. (2005) Fibroblast Growth Factor-23 Is Regulated by 1α,25-Dihydroxyvitamin D. Journal of Bone and Mineral Research 20:11, 1944-1950
CrossRef34
Michel Laroche, Jean-Frederic Boyer. (2005) Phosphate diabetes, tubular phosphate reabsorption and phosphatonins. Joint Bone Spine 72:5, 376-381
CrossRef35
T. Berndt. (2005) The Phosphatonins and the Regulation of Phosphorus Homeostasis. International Bone and Mineral Society Knowledge Environment 2:6, 5-16
CrossRef36
Xijie Yu, Kenneth E. White. (2005) FGF23 and disorders of phosphate homeostasis. Cytokine & Growth Factor Reviews 16:2, 221-232
CrossRef37
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CrossRef38
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Peter S.N. Rowe, Ian R. Garrett, Patricia M. Schwarz, David L. Carnes, Eileen M. Lafer, Gregory R. Mundy, Gloria E. Gutierrez. (2005) Surface plasmon resonance (SPR) confirms that MEPE binds to PHEX via the MEPE–ASARM motif: a model for impaired mineralization in X-linked rickets (HYP). Bone 36:1, 33-46
CrossRef40
Claudio Ungari, Giovanni Rocchi, Claudio Rinna, Alessandro Agrillo, Alessandro Lattanzi, Mario Pagnoni. (2004) Hypophosphaturic Mesenchymal Tumor of the Ethmoid Associated With Oncogenic Osteomalacia. Journal of Craniofacial Surgery 15:3, 523-527
CrossRef41
L.M Ward, F Rauch, K.E White, G Filler, M.A Matzinger, M Letts, R Travers, M.J Econs, F.H Glorieux. (2004) Resolution of severe, adolescent-onset hypophosphatemic rickets following resection of an FGF-23-producing tumour of the distal ulna. Bone 34:5, 905-911
CrossRef42
Eiji Takeda, Hironori Yamamoto, Kunitaka Nashiki, Tadatoshi Sato, Hidekazu Arai, Yutaka Taketani. (2004) Inorganic phosphate homeostasis and the role of dietary phosphorus. Journal of Cellular and Molecular Medicine 8:2, 191-200
CrossRef43
Andrew L. Folpe, Julie C. Fanburg-Smith, Steven D. Billings, Michele Bisceglia, Franco Bertoni, Justin Y. Cho, Michael J. Econs, Carrie Y. Inwards, Suzanne M. Jan de Beur, Thomas Mentzel, Elizabeth Montgomery, Michal Michal, Markku Miettinen, Stacey E. Mills, John D. Reith, John X. O'Connell, Andrew E. Rosenberg, Brian P. Rubin, Donald E. Sweet, Tuyethoa N. Vinh, Lester E. Wold, Brett M. Wehrli, Kenneth E. White, Richard J. Zaino, Sharon W. Weiss. (2004) Most Osteomalacia-associated Mesenchymal Tumors Are a Single Histopathologic Entity. The American Journal of Surgical Pathology 28:1, 1-30
CrossRef44
Susan C. Schiavi, Rajiv Kumar. (2004) The phosphatonin pathway: New insights in phosphate homeostasis. Kidney International 65:1, 1-14
CrossRef45
Eiji Takeda, Yutaka Taketani, Naoki Sawada, Tadatoshi Sato, Hironori Yamamoto. (2004) The regulation and function of phosphate in the human body. BioFactors 21:1-4, 345-355
CrossRef46
Eberhard Ritz, Volker Haxsen, Martin Zeier. (2003) Disorders of phosphate metabolism—pathomechanisms and management of hypophosphataemic disorders. Best Practice & Research Clinical Endocrinology & Metabolism 17:4, 547-558
CrossRef47
Theresa Berndt, Theodore A. Craig, Ann E. Bowe, John Vassiliadis, David Reczek, Richard Finnegan, Suzanne M. Jan De Beur, Susan C. Schiavi, Rajiv Kumar. (2003) Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. Journal of Clinical Investigation 112:5, 785-794
CrossRef48
R. J. Singh, R. Kumar. (2003) Fibroblast Growth Factor 23 Concentrations in Humoral Hypercalcemia of Malignancy and Hyperparathyroidism. Mayo Clinic Proceedings 78:7, 826-829
CrossRef49
Rajiv Kumar. (2002) New insights into phosphate homeostasis: fibroblast growth factor 23 and frizzled-related protein-4 are phosphaturic factors derived from tumors associated with osteomalacia. Current Opinion in Nephrology and Hypertension 11:5, 547-553
CrossRef50
Seiji Fukumoto, Takeyoshi Yamashita. (2002) Fibroblast growth factor-23 is the phosphaturic factor in tumor-induced osteomalacia and may be phosphatonin. Current Opinion in Nephrology and Hypertension 11:4, 385-389
CrossRef51
Susan C. Schiavi, Orson W. Moe. (2002) Phosphatonins: a new class of phosphate-regulating proteins. Current Opinion in Nephrology and Hypertension 11:4, 423-430
CrossRef52
Suzanne M. Jan De Beur, Richard B. Finnegan, John Vassiliadis, Brian Cook, Dana Barberio, Scott Estes, Partha Manavalan, Joseph Petroziello, Stephen L. Madden, Justin Y. Cho, Rajiv Kumar, Michael A. Levine, Susan C. Schiavi. (2002) Tumors Associated With Oncogenic Osteomalacia Express Genes Important in Bone and Mineral Metabolism. Journal of Bone and Mineral Research 17:6, 1102-1110
CrossRef53
Seufert, Jochen, Ebert, Katja, Müller, Justus, Eulert, Jochen, Hendrich, Christian, Werner, Edgar, Schütze, Norbert, Schulz, Georg, Kenn, Werner, Richtmann, Hubert, Palitzsch, Klaus-Dieter, Jakob, Franz, . (2001) Octreotide Therapy for Tumor-Induced Osteomalacia. New England Journal of Medicine 345:26, 1883-1888
Full Text54
Kenneth E White, Gwenaelle Carn, Bettina Lorenz-Depiereux, Anna Benet-Pages, Tim M Strom, Michael J Econs. (2001) Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney International 60:6, 2079-2086
CrossRef55
M.R John, H Wickert, K Zaar, K.B Jonsson, A Grauer, P Ruppersberger, H Schmidt-Gayk, H Murer, R Ziegler, E Blind. (2001) A case of neuroendocrine oncogenic osteomalacia associated with a PHEX and fibroblast growth factor-23 expressing sinusidal malignant schwannoma. Bone 29:4, 393-402
CrossRef56
Jacob Green, Hilla Debby, Eleanor Lederer, Moshe Levi, Hubert K. Zajicek, Tova Bick. (2001) Evidence for a PTH-independent humoral mechanism in post-transplant hypophosphatemia and phosphaturia. Kidney International 60:3, 1182-1196
CrossRef57
Jeong Mi Park, Young Kyun Woo, Moo Il Kang, Chang Suk Kang, Seong Tae Hahn. (2001) Oncogenic osteomalacia associated with soft tissue chondromyxoid fibroma. European Journal of Radiology 39:2, 69-72
CrossRef58
Michael P. Whyte, Michelle N. Podgornik, Valerie A. Wollberg, Mark C. Eddy, William H. McAlister. (2001) Pseudo-(Tumor-Induced) Rickets. Journal of Bone and Mineral Research 16:8, 1564-1571
CrossRef59
Dominique Prié, Vincent Ravery, Laurent Boccon-Gibod, Gérard Friedlander. (2001) Frequency of renal phosphate leak among patients with calcium nephrolithiasis. Kidney International 60:1, 272-276
CrossRef60
Moshe Levi. (2001) Post-transplant hypophosphatemia. Kidney International 59:6, 2377-2387
CrossRef61
L. Argiro, M. Desbarats, F.H. Glorieux, B. Ecarot. (2001) MEPE, the Gene Encoding a Tumor-Secreted Protein in Oncogenic Hypophosphatemic Osteomalacia, Is Expressed in Bone. Genomics 74:3, 342-351
CrossRef62
Ann E. Bowe, Richard Finnegan, Suzanne M. Jan de Beur, Justin Cho, Michael A. Levine, Rajiv Kumar, Susan C. Schiavi. (2001) FGF-23 Inhibits Renal Tubular Phosphate Transport and Is a PHEX Substrate. Biochemical and Biophysical Research Communications 284:4, 977-981
CrossRef63
A.E Nelson, J.J Hogan, I.A Holm, B.G Robinson, R.S Mason. (2001) Phosphate wasting in oncogenic osteomalacia: phex is normal and the tumor-derived factor has unique properties. Bone 28:4, 430-439
CrossRef64
Yumie Rhee, Jong Doo Lee, Kyoo Ho Shin, Hyun Chul Lee, Kap Bum Huh, Sung-Kil Lim. (2001) Oncogenic osteomalacia associated with mesenchymal tumour detected by indium-111 octreotide scintigraphy. Clinical Endocrinology 54:4, 551-554
CrossRef65
Ze’ev Hochberg. (2001) Rickets: it’s not just vitamin D deficiency. Current Opinion in Endocrinology & Diabetes 8:1, 23-28
CrossRef66
Cabot, Richard C.Scully, Robert E., Mark, Eugene J., McNeely, William F., Shepard, Jo-Anne O., Ebeling, Sally H.Ellender, Stacey M.Peters, Christine C., Einhorn, Thomas A.Nielsen, G. Petur. (2001) Case 1-2001. New England Journal of Medicine 344:2, 124-131
Full Text67
Evangelos Zoidis, Jürgen Zapf, Christoph Schmid. (2000) Phex cDNA cloning from rat bone and studies on Phex mRNA expression: tissue-specificity, age-dependency, and regulation by insulin-like growth factor (IGF) I in vivo. Molecular and Cellular Endocrinology 168:1-2, 41-51
CrossRef68
R Kumar. (2000) Tumor-induced osteomalacia and the regulation of phosphate homeostasis. Bone 27:3, 333-338
CrossRef69
Linda A. DiMeglio, Kenneth E. White, Michael J. Econs. (2000) DISORDERS OF PHOSPHATE METABOLISM. Endocrinology & Metabolism Clinics of North America 29:3, 591-609
CrossRef70
Peter S.N Rowe, Priyal A de Zoysa, Rong Dong, Huei Rong Wang, Kenneth E White, Michael J Econs, Claudine L Oudet. (2000) MEPE, a New Gene Expressed in Bone Marrow and Tumors Causing Osteomalacia. Genomics 67:1, 54-68
CrossRef71
Marc K Drezner. (2000) PHEX gene and hypophosphatemia. Kidney International 57:1, 9-18
CrossRef72
Teresa Nesbitt, Ikuma Fujiwara, Ronald Thomas, Zhou-Sheng Xiao, L. Darryl Quarles, Marc K. Drezner. (1999) Coordinated Maturational Regulation of PHEX and Renal Phosphate Transport Inhibitory Activity: Evidence for the Pathophysiological Role of PHEX in X-Linked Hypophosphatemia. Journal of Bone and Mineral Research 14:12, 2027-2035
CrossRef73
Janet E. Henderson, DaShen Wang. (1999) Disorders of phosphate metabolism and metabolic bone disease. Current Opinion in Orthopedics 10:5, 344-353
CrossRef74
S. Dutta, A. Bagga. (1999) McCune albright syndrome and hypophosphatemic rickets. The Indian Journal of Pediatrics 66:4, 628-631
CrossRef75
M.J. Econs. (1999) New insights into the pathogenesis of inherited phosphate wasting disorders. Bone 25:1, 131-135
CrossRef76
Epstein, Franklin H., , Scheinman, Steven J., Guay-Woodford, Lisa M., Thakker, Rajesh V., Warnock, David G., . (1999) Genetic Disorders of Renal Electrolyte Transport. New England Journal of Medicine 340:15, 1177-1187
Full Text77
Peter S. N. Rowe. (1998) X-linked rickets and tumor-acquired osteomalacia:PHEX and the missing link. Clinical and Experimental Nephrology 2:3, 183-193
CrossRef78
Peter S.N. Rowe. (1998) The role of the PHEX gene (PEX) in families with X-linked hypophosphataemic rickets. Current Opinion in Nephrology and Hypertension 7:4, 367-376
CrossRef79
Mark R. Haussler, G. Kerr Whitfield, Carol A. Haussler, Jui-Cheng Hsieh, Paul D. Thompson, Sanford H. Selznick, Carlos Encinas Dominguez, Peter W. Jurutka. (1998) The Nuclear Vitamin D Receptor: Biological and Molecular Regulatory Properties Revealed. Journal of Bone and Mineral Research 13:3, 325-349
CrossRef80
Toru Hirano, Tatsuhiko Tanizawa, Naoto Endo, Hideaki E. Takahashi, Takashi Morita. (1997) Oncogenic osteomalacia: Pre- and postoperative histomorphometric studies. Journal of Bone and Mineral Metabolism 15:4, 227-231
CrossRef81
Mahmoud Loghman-Adham, Daniel Walton, Per-Henrik Iverius, Andrew Deiss, Joseph A. Knight, Alfred K. Cheung. (1997) Spurious hypophosphatemia in a patient with multiple myeloma. American Journal of Kidney Diseases 30:4, 571-575
CrossRef82
Elizabeth Shane, May Parisien, Janet E. Henderson, David W. Dempster, Frieda Feldman, Mark A. Hardy, Jack F. Tohme, Andrew C. Karaplis, Thomas L. Clemens. (1997) Tumor-Induced Osteomalacia: Clinical and Basic Studies. Journal of Bone and Mineral Research 12:9, 1502-1511
CrossRef83
David M. Reese, Peter J. Rosen. (1997) Oncogenic Osteomalacia Associated With Prostate Cancer. The Journal of Urology887
CrossRef84
Anne E Nelson, Rebecca S Mason, Bruce G Robinson. (1997) The PEX gene: not a simple answer for X-linked hypophosphataemic rickets and oncogenic osteomalacia. Molecular and Cellular Endocrinology 132:1-2, 1-5
CrossRef85
David M. Reese, Peter J. Rosen. (1997) Oncogenic Osteomalacia Associated With Prostate Cancer. The Journal of Urology 158:3, 887
CrossRef86
Shixin Wu, Marvin Grieff, Alex J. Brown. (1997) Regulation of Renal Vitamin D-24-Hydroxylase by Phosphate: Effects of Hypophysectomy, Growth Hormone and Insulin-like Growth Factor I. Biochemical and Biophysical Research Communications 233:3, 813-817
CrossRef87
Tony Dash, Mark G. Parker, Richard A. Lafayette. (1997) Profound hypophosphatemia and isolated hyperphosphaturia in two cases of multiple myeloma. American Journal of Kidney Diseases 29:3, 445-448
CrossRef88
Harriet S. Tenenhouse. (1997) Cellular and Molecular Mechanisms of Renal Phosphate Transport. Journal of Bone and Mineral Research 12:2, 159-164
CrossRef89
Anne E. Nelson, Heeja J. Namkung, John Patava, Margaret R. Wilkinson, Andy C-M. Chang, Roger R. Reddel, Bruce G. Robinson, Rebecca S. Mason. (1996) Characteristics of tumor cell bioactivity in oncogenic osteomalacia. Molecular and Cellular Endocrinology 124:1-2, 17-23
CrossRef90
Daniel Lajeunesse, R A Meyer, L Hamel. (1996) Direct demonstration of a humorally-mediated inhibition of renal phosphate transport in the Hyp mouse. Kidney International 50:5, 1531-1538
CrossRef91
Yousri M. Barri, James P. Knochel. (1996) HYPERCALCEMIA AND ELECTROLYTE DISTURBANCES IN MALIGNANCY. Hematology/Oncology Clinics of North America 10:4, 775-790
CrossRef92
Franklin H Epstein. (1996) Contributions of clinical medicine to renal physiology. Kidney International 49:6, 1534-1538
CrossRef93
Michael J Econs. (1996) Positional cloning of the HYP gene: A review. Kidney International 49:4, 1033-1037
CrossRef94
Stephen A Kempson. (1996) Peptide hormone action on renal phosphate handling. Kidney International 49:4, 1005-1009
CrossRef95
Takahiro Tsu Jimura, Katsuhiko Sakaguchi, Katsuyuki Aozasa. (1996) Phosphaturic mesenchymal tumor, mixed connective tissue variant (oncogenic osteomaiacia). Pathology International 46:3, 238-241
CrossRef96
P.S.N. Rowe, A.C.M. Ong, F.J. Cockerill, J.N. Goulding, M. Hewison. (1996) Candidate 56 and 58 kDa protein(s) responsible for mediating the renal defects in oncogenic hypophosphatemic osteomalacia. Bone 18:2, 159-169
CrossRef97
Bart L. Clarke, Alan G. Wynne, David M. Wilson, Lorraine A. Fitzpatrick. (1995) Osteomalacia associated with adult Fanconi's syndrome: clinical and diagnostic features. Clinical Endocrinology 43:4, 479-490
CrossRef98
Teresa Nesbitt, Michael J. Econs, Jong K. Byun, Josée Martel, Harriet S. Tenenhouse, Marc K. Drezner. (1995) Phosphate transport in immortalized cell cultures from the renal proximal tubule of normal and Hyp Mice: Evidence That the HYP gene locus product is an extrarenal factor. Journal of Bone and Mineral Research 10:9, 1327-1333
CrossRef99
Teresa Nesbitt, Marc K. Drezner, Sandy C. Marks, Mary E. Jackson, Carole A. Mackay. (1995) Normalization of mineral homeostasis after reversal of osteopetrosis. Journal of Bone and Mineral Research 10:7, 1116-1121
CrossRef100
B. Eyskens, W. Proesmans, B. Damme, L. Lateur, R. Bouillon, M. Hoogmartens. (1995) Tumour-induced rickets: A case report and review of the literature. European Journal of Pediatrics 154:6, 462-468
CrossRef101
(1994) Oncogenic Osteomalacia. New England Journal of Medicine 331:15, 1023-1023
Full Text102
Econs, Michael J., Drezner, Marc K., . (1994) Tumor-Induced Osteomalacia -- Unveiling a New Hormone. New England Journal of Medicine 330:23, 1679-1681
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