Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse.

Marie, Pierre J.; Travers, Rose; Glorieux, Francis H.

doi:10.1172/jci110110

Cited by 55 publications

(34 citation statements)

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“…Several identical mutations including R291X were observed in different ethnic populations (19,21,22). Moreover, the frequency of de novo mutations has been estimated as approximately 20% (15,16,18). These findings suggest that the PHEX gene appears to be particularly prone to mutations for unknown reasons.…”

Section: Discussionmentioning

confidence: 94%

“…Moreover, the mRNA of PHEX in human fetal tissue has been found to be preferentially expressed in early bone development (9). In the hypophosphatemic (Hyp) mouse model of XLH, the murine phosphate-regulating gene (Pex) mRNA expression is also seen mainly in bone (9), and bone formation is not normalized after transplantation of bone cells from Hyp mice into the normal mice (15)(16)(17)(18). These findings indicate that PHEX protein not only has endopeptidase-like function, but is also important for bone formation (9,(15)(16)(17)(18).…”

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confidence: 99%

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Three Novel PHEX Gene Mutations in Japanese Patients with X-Linked Hypophosphatemic Rickets

et al. 2000

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Section: Discussionmentioning

confidence: 94%

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confidence: 99%

Three Novel PHEX Gene Mutations in Japanese Patients with X-Linked Hypophosphatemic Rickets

et al. 2000

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“…Inefficient re-absorption of phosphate by the kidney is associated with defective mineralization of the skeleton, which manifests as rickets in children and osteomalacia in adults. High doses of oral phosphate have been shown to be as effective as vitamin D in healing rachitic lesions in humans (15), as well as in rats (16) and mice (17). By adapting micropuncture techniques to sample cartilage lymph in the growth plates of rachitic rats, it was shown that phosphate is preferentially sequestered relative to calcium in the zone of hypertrophic cells surrounded by unmineralized cartilage (18).…”

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confidence: 99%

Alterations in the Sensing and Transport of Phosphate and Calcium by Differentiating Chondrocytes

Wang¹,

Canaff²,

Davidson³

et al. 2001

Journal of Biological Chemistry

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During endochondral bone formation and fracture healing, cells committed to chondrogenesis undergo a temporally restricted program of differentiation that is characterized by sequential changes in their phenotype and gene expression. This results in the manufacture, remodeling, and mineralization of a cartilage template on which bone is laid down. Articular chondrocytes undergo a similar but restricted differentiation program that does not proceed to mineralization, except in pathologic conditions such as osteoarthritis. The pathogenesis of disorders of cartilage development and metabolism, including osteochondrodysplasia, fracture non-union, and osteoarthritis remain poorly defined. We used the CFK2 model to examine the potential roles of phosphate and calcium ions in the regulatory pathways that mediate chondrogenesis and cartilage maturation. Differentiation was monitored over a 4-week period using a combination of morphological, biochemical, and molecular markers that have been characterized in vivo and in vitro. CFK2 cells expressed the type III sodiumdependent phosphate transporters Glvr-1 and Ram-1, as well as a calcium-sensing mechanism. Regulated expression and activity of Glvr-1 by extracellular phosphate and parathyroid hormone-related protein was restricted to an early stage of CFK2 differentiation, as evidenced by expression of type II collagen, proteoglycan, and Ihh. On the other hand, regulated expression and activity of a calcium-sensing receptor by extracellular calcium was most evident after 2 weeks of differentiation, concomitant with an increase in type X collagen expression, alkaline phosphatase activity and parathyroid hormone/parathyroid hormone-related protein receptor expression. On the basis of these temporally restricted changes in the sensing and transport of phosphate and calcium, we predict that extracellular phosphate plays a role in the commitment of chondrogenic cells to differentiation, whereas extracellular calcium plays a role at a later stage in their differentiation program.Bones of the mammalian skeleton develop by two distinct mechanisms. Intramembranous bone, exemplified by the frontal and parietal bones of the cranial vault, is formed when mesenchymal stem cells differentiate directly into bone-forming osteoblasts. The bones at the base of the skull, including parts of the temporal and occipital bones, as well as the vertebral column and the appendicular skeleton, are formed by endochondral ossification. These "cartilage bones" are formed when mesenchymal precursors condense and differentiate into chondrogenic cells that deposit and mineralize a cartilage matrix (1), which is remodeled by catabolic cells (chondroclasts) brought in by the vasculature (2). The remodeled cartilage then forms the template on which bone is deposited by osteoblastic cells. The same process of endochondral ossification occurs in the adult during fracture healing. Although chondrocytes involved in endochondral ossification and those present in articular cartilage arise from the same lineage and ...

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“…The defective renal phosphate transport in Hyp mice (3) has been attributed to decreased renal expression of the Na-Pi cotransporter gene and immunoreactive protein (4) and is thought to result from the effect of a humoral factor (5,6). The failure of phosphate therapy and the need for concurrent administration of supraphysiological doses of 1,25-(OH) 2 D 3 to correct the bone osteomalacic lesions in affected patients (7,8) and mice (9,10) have indicated that hypophosphatemia is not the sole cause of the defective bone mineralization. Evidence has been provided for an associated osteoblast dysfunction in this disorder.…”

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confidence: 99%

1,25-(OH)2D3 Down-Regulates Expression of Phex, a Marker of the Mature Osteoblast

Ecarot

1999

Endocrinology

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Mutations in the PHEX/Phex gene, which encodes for a protein with homology to neutral endopeptidases, are responsible for human and murine X-linked hypophosphatemia. The present study examined Phex messenger RNA (mRNA) and protein expression in cultured osteoblasts and its regulation by 1,25-(OH) 2 D 3 . Phex mRNA levels were quantitated on Northern blots by densitometric analysis relatively to GAPDH mRNA levels. Immunoreactive Phex protein levels were evaluated by immunoprecipitation using a polyclonal rabbit antiserum raised against a mouse Phex carboxy-terminal peptide.␤-Glycerophosphate-induced matrix mineralization in primary osteoblast cultures was associated with significant increases in Phex mRNA and protein. Phex mRNA and protein levels were low or undetectable in proliferating preosteoblastic MC3T3-E1 cells and dramatically increased concomitantly with initiation of matrix mineralization. The pattern of Phex expression, however, was similar in nonmineralizing cultures grown in the absence of ␤-glycerophosphate, indicating that the induction of Phex expression in MC3T3-E1 cells was related to cell differentiation rather than matrix mineralization. 1,25-(OH) 2 D 3 inhibited mineral deposition and down-regulated Phex mRNA and protein expression in a time-and dose-dependent manner.These results indicate that Phex is a marker of the fully differentiated osteoblast and that its expression is stimulated during ␤-glycerophosphate-induced mineralization in primary osteoblast cultures and down-regulated by 1,25-(OH) 2 D 3 , an inhibitor of matrix mineralization. These findings add support for Phex having an important role in bone mineralization. (Endocrinology 140: 1192(Endocrinology 140: -1199(Endocrinology 140: , 1999 X -LINKED hypophosphatemia is associated with hypophosphatemia that results from impaired renal phosphate reabsorption, rickets, and osteomalacia that lead to stunted growth and skeletal deformities (1). Despite extensive investigations of the murine homologue, the Hyp mouse (2), the underlying mechanism for the bone and renal abnormalities is not understood. The defective renal phosphate transport in Hyp mice (3) has been attributed to decreased renal expression of the Na-Pi cotransporter gene and immunoreactive protein (4) and is thought to result from the effect of a humoral factor (5, 6). The failure of phosphate therapy and the need for concurrent administration of supraphysiological doses of 1,25-(OH) 2 D 3 to correct the bone osteomalacic lesions in affected patients (7,8) and mice (9, 10) have indicated that hypophosphatemia is not the sole cause of the defective bone mineralization. Evidence has been provided for an associated osteoblast dysfunction in this disorder. They include the presence of characteristic hypomineralized periosteocytic lesions in cortical bone of XLH patients (11) that do not completely disappear in treated patients despite normalization of the mineralization process (12) and the failure of Hyp bone cells to produce normal bone when transplanted into norma...

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Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse.

Cited by 55 publications

References 12 publications

Three Novel PHEX Gene Mutations in Japanese Patients with X-Linked Hypophosphatemic Rickets

Three Novel PHEX Gene Mutations in Japanese Patients with X-Linked Hypophosphatemic Rickets

Alterations in the Sensing and Transport of Phosphate and Calcium by Differentiating Chondrocytes

1,25-(OH)2D3 Down-Regulates Expression of Phex, a Marker of the Mature Osteoblast

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