Pex Gene Deletions in Gy and Hyp Mice Provide Mouse Models for X-Linked Hypophosphatemia

Strom, Tim M.; Francis, Fiona; Lorenz, Bettina; Böddrich, Annett; Econs, Michael J.; Lehrach, Hans; Meitinger, Thomas

doi:10.1093/hmg/6.2.165

Cited by 188 publications

(121 citation statements)

References 30 publications

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“…These findings establish that FGF23 C-terminal peptides counteract or cancel out FGF23's phosphaturic action mediated through NaP i -2A and NaP i -2C. ( [26][27][28][29]. XLH is an inherited phosphate wasting disorder associated with high FGF23, which is thought to be due to reduced clearance of FGF23 from the circulation.…”

Section: Resultsmentioning

confidence: 79%

Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation

Goetz

Nakada²,

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

343

335

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Fibroblast growth factor (FGF) 23 inhibits renal phosphate reabsorption by activating FGF receptor (FGFR) 1c in a Klotho-dependent fashion. The phosphaturic activity of FGF23 is abrogated by proteolytic cleavage at the RXXR motif that lies at the boundary between the FGF core homology domain and the 72-residue-long C-terminal tail of FGF23. Here, we show that the soluble ectodomains of FGFR1c and Klotho are sufficient to form a ternary complex with FGF23 in vitro. The C-terminal tail of FGF23 mediates binding of FGF23 to a de novo site generated at the composite FGFR1c-Klotho interface. Consistent with this finding, the isolated 72-residue-long C-terminal tail of FGF23 impairs FGF23 signaling by competing with full-length ligand for binding to the binary FGFR-Klotho complex. Injection of the FGF23 C-terminal tail peptide into healthy rats inhibits renal phosphate excretion and induces hyperphosphatemia. In a mouse model of renal phosphate wasting attributable to high FGF23, the FGF23 C-terminal peptide reduces phosphate excretion, leading to an increase in serum phosphate concentration. Our data indicate that proteolytic cleavage at the RXXR motif abrogates FGF23 activity by a dual mechanism: by removing the binding site for the binary FGFRKlotho complex that resides in the C-terminal region of FGF23, and by generating an endogenous inhibitor of FGF23. We propose that peptides derived from the C-terminal tail of FGF23 or peptidomimetics and small-molecule organomimetics of the C-terminal tail can be used as therapeutics to treat renal phosphate wasting.

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Section: Resultsmentioning

confidence: 79%

Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation

Goetz

Nakada²,

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

343

335

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“…It has been suggested that osteocytes are mediators of mechanical and hormonal stimulations to control the activity of both osteoblasts and osteoclasts (1). Osteocytes are regulators of mineralization and mineral homeostasis (2,3), and by controlling Sost expression also act as modulators of Wnt signaling (4).…”

mentioning

confidence: 99%

Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice

Zhou¹,

Zhang²,

Feng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

286

255

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The transcription factor Osterix (Osx) is required for osteoblast differentiation and bone formation during embryonic development, but it is not known whether Osx has an essential function in postnatal bone growth and in bone homeostasis. Conditional deletion of Osx at several time points postnatally revealed that Osx was essential for osteoblast differentiation and new bone formation in growing and adult bones. Additionally, inactivation of Osx in bones severely disrupted the maturation, morphology, and function of osteocytes. These findings identify Osx as having an essential role in the cell-specific genetic program of osteocytes. Interestingly, Osx inactivation also led to the massive accumulation of unresorbed calcified cartilage in a large area below the growth plate of endochondral bones. This specific area was also marked by an unanticipated almost complete lack of bone marrow cells and a marked decrease in the density and size of osteoclasts. This diminished density of osteoclasts could contribute to the lack of resorption of mineralized cartilage. In addition, we speculate that the abnormally accumulated, mainly naked cartilage represents an unfavorable substrate for osteoclasts. Our study identifies Osx as an essential multifunctional player in postnatal bone growth and homeostasis.osteoblast differentiation | skeletal homeostasis | transcription factor | osteocyte | cartilage resorption T he identification of master transcription factors essential for osteoblast differentiation and bone formation during embryonic development has greatly advanced our knowledge of bone biology. However, the transcriptional control of postnatal bone formation and homeostasis remain poorly understood. Normal skeletal growth and homeostasis depends on the coordinated activities of three types of bone cells: osteoblasts, osteoclasts, and osteocytes. Factors secreted by the mesenchyme-derived osteoblasts also control the differentiation and activity of the boneresorbing osteoclasts derived from hematopoietic stem cells. Conversely, bone resorption by osteoclasts releases factors important for bone formation. Osteocytes, which make up over 90-95% of all bone cells in adult animals, are derived from mature osteoblasts and are embedded inside the bone matrix. It has been suggested that osteocytes are mediators of mechanical and hormonal stimulations to control the activity of both osteoblasts and osteoclasts (1). Osteocytes are regulators of mineralization and mineral homeostasis (2, 3), and by controlling Sost expression also act as modulators of Wnt signaling (4).Three transcription factors [β-catenin, Runx2, and Osterix (Osx)] are required for osteoblast differentiation and bone formation during embryonic development (5-9). Osx, which acts downstream of Runx2, is a zinc-finger-containing transcription factor essential for embryonic osteoblast differentiation and bone formation (8). During development, Osx is specifically expressed in osteoblast lineage cells and, at lower levels, in prehypertrophic chondrocytes, but not in ...

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“…Hyp mice harbor a large 3' deletion in the Phex gene (62,63), whereas Gy mice have a deletion in the 5' region that includes the upstream gene, spermine synthase (63). Gy is thus a contiguous gene deletion syndrome, which may explain why these mutants exhibit phenotypic features that are not apparent in Hyp mice (see reference 51).…”

Section: X-linked Hypophosphatemiamentioning

confidence: 99%

Disorders of Renal Tubular Phosphate Transport

Tenenhouse¹,

Murer²

2003

Journal of the American Society of Nephrology

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The kidney plays a major role in the maintenance of inorganic phosphate (P i ) homeostasis and, as such, ensures that an adequate supply of this ubiquitous anion is available for proper cellular function and skeletal mineralization. Physiologic studies have revealed that the bulk of filtered P i is reabsorbed in the proximal tubule, with higher rates of reabsorption in the early segments and in deep nephrons. This review will summarize the progress that has been made in the molecular identification and regulation of renal P i transporters. In addition, it will focus on the pathophysiology of inherited (X-linked hypophosphatemia [XLH], autosomal dominant hypophosphatemic rickets [ADHR], and hereditary hypophosphatemic rickets with hypercalciuria [HHRH]) and acquired (oncogenic hypophosphatemic osteomalacia [OHO]) renal P i wasting disorders, and discuss the role of two novel P i -regulating genes, PHEX and FGF-23, in the regulation of P i homeostasis. For recent reviews see references 1-5. Cellular Mechanism of Proximal Tubular P i ReabsorptionP i reabsorption in the proximal tubule is mediated by Na ϩ -dependent, secondary-active transport mechanisms. Influx of P i from the tubular lumen into the epithelial cell involves brush border membrane-associated Na/P i cotransporter(s) which are rate-limiting and targets for physiologic/pathophysiologic regulation. Efflux of P i across the basolateral membrane may involve an anion exchange mechanism and/or a "P i leak" to complete transcellular reabsorptive flux, and a Na ϩ -dependent P i uptake mechanism to guarantee P i uptake from the interstitium if apical influx is insufficient to maintain cellular metabolism [for review see (1)].

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Pex Gene Deletions in Gy and Hyp Mice Provide Mouse Models for X-Linked Hypophosphatemia

Cited by 188 publications

References 30 publications

Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation

Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation

Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice

Disorders of Renal Tubular Phosphate Transport

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