Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol.

Harrell, R. Mack; Lyles, Kenneth W.; Harrelson, John M.; Friedman, Nancy; Drezner, Marc K.

doi:10.1172/jci111900

Cited by 126 publications

(64 citation statements)

References 36 publications

(21 reference statements)

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“…Accordingly, increased renal side chain oxidation of 1,25(OH)2D3 in Hyp mice would decrease the effective concentration of 1,25(OH)2D3 available for biological action in the kidney and perhaps other target tissues. Our demonstration of increased renal catabolism of 1,25(OH)2D3 may account, in part, for the inappropriate plasma levels of 1,25(OH)2D in Hyp mice (4) and in patients with X-linked hypophosphatemia (21,22), and may explain why supraphysiological doses of 1,25(OH)2D3 (and phosphate supplementation) are required for correction of bone lesions in these patients (23). Moreover, our results are consistent with the previous demonstration that plasma clearance of high doses of exogenous 1,25(OH)2D3 is more rapid in Hyp mice than in normal littermates (24).…”

Section: Resultsmentioning

confidence: 86%

Increased renal catabolism of 1,25-dihydroxyvitamin D3 in murine X-linked hypophosphatemic rickets.

Tenenhouse¹,

Yip²,

Jones³

1988

J. Clin. Invest.

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Section: Resultsmentioning

confidence: 86%

Increased renal catabolism of 1,25-dihydroxyvitamin D3 in murine X-linked hypophosphatemic rickets.

Tenenhouse¹,

Yip²,

Jones³

1988

J. Clin. Invest.

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“…The present study provides a further rationale for the efficacy of combined therapy with oral phosphate and 1,25(OH)2D3 in the treatment of patients with X-linked hypophosphatemia (2,4,30). Phosphate supplementation, which is necessary to stimulate bone mineralization in these patients, may also play an important role in the maintenance of the steady-state serum concentration of 1,25(OH)2D by reducing its rate of degradation and promoting its rate of synthesis by the kidney.…”

Section: Discussionmentioning

confidence: 84%

Abnormal regulation of renal vitamin D catabolism by dietary phosphate in murine X-linked hypophosphatemic rickets.

Tenenhouse¹,

Jones²

1990

J. Clin. Invest.

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Hyp mice exhibit increased renal catabolism of vitamin D metabolites by the C-24 oxidation pathway (1988. J. Clin. Invest. 81:461-465). To examine the regulatory influence of dietary phosphate on the renal vitamin D catabolic pathway in Hyp mice, we measured C-24 oxidation of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in renal mitochondria isolated from Hyp mice and normal littermates fed diets containing 0.03% (lowPi), 1% (control-Pi), and 1.6% (high-Pi) phosphate. In normal mice the low-Pi diet led to a rise in serum 1,25(OH)2D (22.2±1.8 to 48.1±6.8 pg/ml, P < 0.05) and no change in C-24 oxidation products (0.053±0.006 to 0.066±0.008 pmol/mg protein per min) when compared with the control diet. In Hyp mice the low-Pi diet elicited a fall in serum 1,25(OH)2D (21.9±1.2 to 8.0±0.2 pg/ml, P < 0.05) and a dramatic increase in C-24 oxidation products (0.120±0.017 to 0.526±0.053 pmol/mg protein per min, P < 0.05) when compared with the control diet. The high-Pi diet did not significantly alter serum levels of 1,25(OH)2D or C-24 oxidation products in normal mice. Hyp mice on the high-Pi diet experienced a rise in serum 1,25(0H-1D (21.9±1.2 to 40.4±7.3, P < 0.05) and a fall in C-24 oxidation products (0.120±0.017 to 0.043±0.007 pmol/ mg protein per min, P < 0.05). The present results demonstrate that the defect in C-24 oxidation of 1,25(0H)2D3 in Hyp mice is exacerbated by phosphate depletion and corrected by phosphate supplementation. The data suggest that the disorder in vitamin D metabolism in the mutant strain is secondary to the perturbation in phosphate homeostasis. (J. Clin. Invest. 1990Invest. . 85:1450Invest. -1455.) Hyp mouse-1,25-dihydroxyvitamin D3 * 1,24,25-trihydroxyvitamin D3 -C-24 oxidation -25-hydroxyvitamin D3-24-hydroxylase

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“…In hyp mice and in humans with Xlinked rickets, the mineralization defect is not corrected by dietary phosphate supplementation but also requires supra-physiological doses of calcitriol [8,11,14,15,49,50,60]. Indeed, early and classic studies with hyp mice and human patients were able to show that although dietary phosphate supplementation corrects rickets and the endochondral calcification defect, it does not correct the endosteal mineralization defect [19,20,35,[48][49][50]. Also, the dentinal mineralization defects in the hyp mouse are recently reported as due to intrinsic odontoblast defects and independent of serum phosphate levels [58].…”

Section: Discussionmentioning

confidence: 99%

Correction of the mineralization defect in hyp mice treated with protease inhibitors CA074 and pepstatin

Rowe

Matsumoto

et al. 2006

Bone

118

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Increased expression of several osteoblastic proteases and MEPE (a bone matrix protein) occurs in X-linked hypophosphatemic rickets (hyp). This is associated with an increased release of a protease-resistant MEPE peptide (ASARM peptide), a potent inhibitor of mineralization. Cathepsin B cleaves MEPE releasing ASARM peptide and hyp osteoblast/osteocyte cells hypersecrete cathepsin D, an activator of cathepsin B. Our aims were to determine whether cathepsin inhibitors correct the mineralization defect in vivo and whether hyp-bone ASARM peptide levels are reduced after protease treatment. Normal littermates and hyp mice (n = 6) were injected intraperitoneally once a day for 4 weeks with pepstatin, CAO74 or vehicle. Animals were then sacrificed and bones plus serum removed for comprehensive analysis. All hyp mice groups (treated and untreated) remained hypophosphatemic with serum 1,25 vitamin D3 inappropriately normal. Serum PTH was significantly elevated in all hyp mice groups relative to normal mice (P = 0.0017). Untreated hyp mice had six-fold elevated levels of serum alkaline-phosphatase and twofold elevated levels of ASARM peptides relative to normal mice (P < 0.001). In contrast, serum alkaline phosphatase and serum ASARM peptides were significantly reduced (normalized) in hyp mice treated with CA074 or pepstatin. Serum FGF23 levels remained high in all hyp animal groups (P < 0.0001). Hyp mice treated with protease inhibitors showed dramatic reductions in unmineralized osteoid (femurs) compared to control hyp mice (Goldner staining). Also, hyp animals treated with protease inhibitors showed marked and significant improvements in growth plate width (42%), osteoid thickness (40%) and cortical area (40%) (P < 0.002). The mineralization apposition rate, bone formation rate and mineralization surface were normalized by protease-treatment. High-resolution pQCT mineral histomorphometry measurements and uCT also confirmed a marked mineralization improvement. Finally, the growth plate and cortical bone of hyp femurs contained a massive accumulation of osteoblast-derived ASARM peptide(s) that was reduced in hyp animals treated with CA074 or pepstatin. This study confirms in vivo administration of cathepsin inhibitors improves bone mineralization in hyp mice. This may be due to a protease inhibitor mediated decrease in proteolytic degradation of the extracellular matrix and a reduced release of ASARM peptides (potent mineralization inhibitors).

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Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol.

Cited by 126 publications

References 36 publications

Increased renal catabolism of 1,25-dihydroxyvitamin D3 in murine X-linked hypophosphatemic rickets.

Increased renal catabolism of 1,25-dihydroxyvitamin D3 in murine X-linked hypophosphatemic rickets.

Abnormal regulation of renal vitamin D catabolism by dietary phosphate in murine X-linked hypophosphatemic rickets.

Correction of the mineralization defect in hyp mice treated with protease inhibitors CA074 and pepstatin

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