Increased Metabolic Rate in X-Linked Hypophosphatemic Mice*

Vaughn, Linda K.; Meyer, Ralph A.; Meyer, Mary C.

doi:10.1210/endo-118-1-441

Cited by 9 publications

(10 citation statements)

References 12 publications

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“…The alterations in oxygen-affinity and glucose-metabolism in hypophosphatemic subjects is due primarily to regulatory abnormalities at the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) step [121]. In line with this, defective ATP synthesis and impaired thermoregulatory regulation with increased metabolic rate and oxygen consumption also occurs with X-linked hypophosphatemic rickets mice (HYP) [49], [123]. Also, our study shows that there is a major reduction in HYP renal and bone GAPDH expression.…”

Section: Discussionsupporting

confidence: 73%

“…As discussed earlier, HYP mice have increased oxygen consumption and metabolic rate consistent with a defect in aerobic metabolism [49]. The increased oxygen consumption is not associated with abnormal thyroid hormone T4 levels, altered body weight or surface to weight ratios.…”

Section: Discussionmentioning

confidence: 56%

“…These mice are murine homologs for X-linked hypophosphatemic rickets (HYP) and are also hyperglycemic, hypoinsulinemic with altered energy metabolism [49]–[53]. The physiological substrate for PHEX is free ASARM-peptide or the ASARM-motif [54]–[66].…”

Section: Introductionmentioning

confidence: 99%

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PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

2014

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ContextPHEX or DMP1 mutations cause hypophosphatemic-rickets and altered energy metabolism. PHEX binds to DMP1-ASARM-motif to form a complex with α5β3 integrin that suppresses FGF23 expression. ASARM-peptides increase FGF23 by disrupting the PHEX-DMP1-Integrin complex. We used a 4.2 kDa peptide (SPR4) that binds to ASARM-peptide/motif to study the DMP1-PHEX interaction and to assess SPR4 for the treatment of energy metabolism defects in HYP and potentially other bone-mineral disorders.DesignSubcutaneously transplanted osmotic pumps were used to infuse SPR4-peptide or vehicle (VE) into wild-type mice (WT) and HYP-mice (PHEX mutation) for 4 weeks.ResultsSPR4 partially corrected HYP mice hypophosphatemia and increased serum 1.25(OH)2D3. Serum FGF23 remained high and PTH was unaffected. WT-SPR4 mice developed hypophosphatemia and hypercalcemia with increased PTH, FGF23 and 1.25(OH)2D3. SPR4 increased GAPDH HYP-bone expression 60× and corrected HYP-mice hyperglycemia and hypoinsulinemia. HYP-VE serum uric-acid (UA) levels were reduced and SPR4 infusion suppressed UA levels in WT-mice but not HYP-mice. SPR4 altered leptin, adiponectin, and sympathetic-tone and increased the fat mass/weight ratio for HYP and WT mice. Expression of perlipin-2 a gene involved in obesity was reduced in HYP-VE and WT-SPR4 mice but increased in HYP-SPR4 mice. Also, increased expression of two genes that inhibit insulin-signaling, ENPP1 and ESP, occurred with HYP-VE mice. In contrast, SPR4 reduced expression of both ENPP1 and ESP in WT mice and suppressed ENPP1 in HYP mice. Increased expression of FAM20C and sclerostin occurred with HYP-VE mice. SPR4 suppressed expression of FAM20C and sclerostin in HYP and WT mice.ConclusionsASARM peptides and motifs are physiological substrates for PHEX and modulate osteocyte PHEX-DMP1-α5β3-integrin interactions and thereby FGF23 expression. These interactions also provide a nexus that regulates bone and energy metabolism. SPR4 suppression of sclerostin and/or sequestration of ASARM-peptides improves energy metabolism and may have utility for treating familial rickets, osteoporosis, obesity and diabetes.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 56%

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PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

2014

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“…These changes are accompanied by reduced renal cortical ribonucleoside triphosphate pools and defective ATP synthesis in hypophosphatemic rickets mice models and humans [66,67]. Defective thermoregulatory control, defective ATP synthesis with increased metabolic rate and oxygen consumption are key features of X-linked hypophosphatemic rickets mice (HYP) [67,68]. This is accompanied by increased osteoblastic pH, increased gluconeogenesis, increased glucose-6-phosphatase activity and decreased renal and bone GAPDH expression [13,14,60].…”

Section: Fam20c Kinase: a Nexus To The Fap/mvp Pathways And Energy Mementioning

confidence: 99%

A unified model for bone–renal mineral and energy metabolism

Rowe

2015

Current Opinion in Pharmacology

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The beginning of the millennium saw the discovery of a new bone-matrix protein, Matrix Extracellular PhosphogloprotEin (MEPE) and an associated C-terminal motif called ASARM. This motif and other distinguishing features occur in a group of proteins called SIBLINGs. These proteins include dentin matrix protein 1 (DMP1), osteopontin, dentin-sialophosphoprotein (DSPP), statherin, bone sialoprotein (BSP) and MEPE. MEPE, DMP1 and ASARM-motifs regulate expression of a phosphate regulating cytokine FGF23. Further, a trimeric interaction between phosphate regulating endopeptidase homolog X-linked (PHEX), DMP1, and α5β3-integrin that occurs on the plasma-membrane of the osteocyte mediates FGF23 regulation (FAP pathway). ASARM-peptides competitively inhibit the trimeric complex and increase FGF23. A second pathway involves specialized structures, matrix vesicles (MVP pathway). This review will discuss the FAP and MVP pathways and present a unified model for mineral and energy metabolism.

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“…It has been reported that oxygen consumption is increased in Hyp mice. 25 Although the exact mechanism by which oxygen consumption is increased remains unknown, this increase in oxygen consumption may reflect a compensatory increase in ATP production. Another possible mechanism is a decrease in ATP consumption.…”

Section: Ionized Calcium Levelsmentioning

confidence: 99%

Blunted effect of parathyroid hormone on adenosine 3′,5′-cyclic monophosphate production is derived from ATP depletion in proximal convoluted tubules of hypophosphatemic mice

Shima

Yamaoka

Nakamura

et al. 2000

Clinical and Experimental Nephrology

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Background.To clarify the pathophysiological features associated with phosphate depletion in hypophosphatemic (Hyp) mice, we examined the effect of extracellular phosphate on parathyroid hormone (PTH)-stimulated adenosine 3Ј,5Ј-cyclic monophosphate (cAMP) production in the proximal convoluted tubules (PCT). Methods. PTH-Stimulated cAMP production and ATP content were determined by radioimmunoassay and luciferinluciferase chemiluminescence methods, respectively. Results. The level of cAMP stimulated by PTH at an extracellular phosphate concentration of 0.78 mM was lower in the Hyp mice than in normal mice. The PTH-stimulated cAMP production in the Hyp mice was increased when the extracellular phosphate concentration was raised. In contrast, an increase in extracellular phosphate did not affect the PTH-stimulated cAMP production in the normal mice. Although the ATP content of the PCT was not different between the normal and Hyp mice immediately after microdissection, after 60 min of incubation, it had decreased to a greater extent in Hyp mice than in the normal animals. Raising the extracellular phosphate concentration from 0.78 to 2.3 mM prevented the decrease in ATP content in Hyp mice, and the intracellular ATP content then became comparable to that in the normal control. Conclusions. These results suggest that ATP content in the PCT tended to be decreased in Hyp mice by a decreased phosphate supply and that the blunted effect of PTH on cAMP production in these mice is due to ATP depletion.

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Increased Metabolic Rate in X-Linked Hypophosphatemic Mice*

Cited by 9 publications

References 12 publications

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

A unified model for bone–renal mineral and energy metabolism

Blunted effect of parathyroid hormone on adenosine 3′,5′-cyclic monophosphate production is derived from ATP depletion in proximal convoluted tubules of hypophosphatemic mice

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