Recent advances in the renal–skeletal–gut axis that controls phosphate homeostasis

Kiela, Pawel R.; Ghishan, Fayez K.

doi:10.1038/labinvest.2008.114

Cited by 52 publications

(45 citation statements)

References 81 publications

(80 reference statements)

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“…Our study shows a significant decrease (Ϫ97%; P Ͻ 0.05) in NPT2A renal phosphate transporter mRNA expression is likely responsible for the lowered serum P i . However, altered NPT2c expression may also be involved since both NPT2a and NPT2c renal phosphate transporters are decreased in several familial and oncogenic hypophosphatemic bone mineralization disorders including HYP, ADHR, ARHR, and TIO (27,45,49,59). As reported previously, we found increased serum ASARM peptides in mice with HYP relative to normal mice (2,9,31,37,48,66).…”

Section: Discussionsupporting

confidence: 83%

ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate

David

Martin

Hedge

et al. 2011

American Journal of Physiology-Renal Physiology

155

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Increased acidic serine aspartate-rich MEPE-associated motif (ASARM) peptides cause mineralization defects in X-linked hypophosphatemic rickets mice (HYP) and "directly" inhibit renal phosphate uptake in vitro. However, ASARM peptides also bind to phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and are a physiological substrate for this bone-expressed, phosphateregulating enzyme. We therefore tested the hypothesis that circulating ASARM peptides also "indirectly" contribute to a bone-renal PHEXdependent hypophosphatemia in normal mice. Male mice (n ϭ 5; 12 wk) were fed for 8 wk with a normal phosphorus and vitamin D 3 diet (1% P i diet) or a reduced phosphorus and vitamin D3 diet (0.1% Pi diet). For the final 4 wk, transplantation of mini-osmotic pumps supplied a continuous infusion of either ASARM peptide (5 mg·day Ϫ1 ·kg Ϫ1 ) or vehicle. HYP, autosomal recessive hypophosphatemic rickets (ARHR), and normal mice (no pumps or ASARM infusion; 0.4% P i diet) were used in a separate experiment designed to measure and compare circulating ASARM peptides in disease and health. ASARM treatment decreased serum phosphate concentration and renal phosphate cotransporter (NPT2A) mRNA with the 1% P i diet. This was accompanied by a twofold increase in serum ASARM and 1,25-dihydroxy vitamin D 3 [1,25 (OH)2D3] levels without changes in parathyroid hormone. For both diets, ASARM-treated mice showed significant increases in serum fibroblast growth factor 23 (FGF23; ϩ50%) and reduced serum osteocalcin (Ϫ30%) and osteopontin (Ϫ25%). Circulating ASARM peptides showed a significant inverse correlation with serum P i and a significant positive correlation with fractional excretion of phosphate. We conclude that constitutive overexpression of ASARM peptides plays a "component" PHEXindependent part in the HYP and ARHR hypophosphatemia. In contrast, with wild-type mice, ASARM peptides likely play a bone PHEX-dependent role in renal phosphate regulation and FGF23 expression. They may also coordinate FGF23 expression by competitively modulating PHEX/DMP1 interactions and thus bone-renal mineral regulation. matrix extracellular phosphoglycoprotein; dentin matrix protein-1; mineralization; osteomalacia; SIBLING proteins; fibroblast growth factor 23; X-linked hypophosphatemic rickets; 1,25 dihydroxy vitamin D3SIBLING PROTEINS MAP to a tightly clustered region on chromosome 4q in humans and chromosome 5 in mice (50). Members include matrix extracellular phosphoglycoprotein (MEPE), dentin matrix protein-1 (DMP1), osteopontin (OPN), bone sialoprotein, enamelin, dentin sialo phosphoprotein, and statherin (19,50). Key features of several SIBLINGs are an acidic serine aspartate-rich MEPE-associated motif (ASARM motif) (50) involved in bone and teeth mineralization (49, 50). Among these proteins, MEPE was cloned from a tumor resected from a patient with tumor-induced osteomalacia (TIO) and hypophosphatemia (50). Increased expression of MEPE occurs in TIO, X-linked hypophosphatemic rickets (HYP), and autosomal r...

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Section: Discussionsupporting

confidence: 83%

ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate

David

Martin

Hedge

et al. 2011

American Journal of Physiology-Renal Physiology

155

View full text Add to dashboard Cite

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“…Our group's findings related to osteoblast/osteocytespecific Phex gene also support at least partial contribution of defective bone formation in colitis. Phex is a critical regulator of systemic P i homeostasis (52), with an intrinsic role in osteoblast mineralization. Immortalized osteoblasts from Phexdeficient Hyp mice fail to mineralize under permissive conditions in vitro (109).…”

Section: Bone Formation Vs Resorption In Animal Models Of Ibdmentioning

confidence: 99%

Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases

Ghishan

Kiela

2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ghishan FK, Kiela PR. Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases. Am J Physiol Gastrointest Liver Physiol 300: G191-G201, 2011. First published November 18, 2010 doi:10.1152/ajpgi.00496.2010.-Chronic inflammatory disorders such as inflammatory bowel diseases (IBDs) affect bone metabolism and are frequently associated with the presence of osteopenia, osteoporosis, and increased risk of fractures. Although several mechanisms may contribute to skeletal abnormalities in IBD patients, inflammation and inflammatory mediators such as TNF, IL-1␤, and IL-6 may be the most critical. It is not clear whether the changes in bone metabolism leading to decreased mineral density are the result of decreased bone formation, increased bone resorption, or both, with varying results reported in experimental models of IBD and in pediatric and adult IBD patients. New data, including our own, challenge the conventional views, and contributes to the unraveling of an increasingly complex network of interactions leading to the inflammationassociated bone loss. Since nutritional interventions (dietary calcium and vitamin D supplementation) are of limited efficacy in IBD patients, understanding the pathophysiology of osteopenia and osteoporosis in Crohn's disease and ulcerative colitis is critical for the correct choice of available treatments or the development of new targeted therapies. In this review, we discuss current concepts explaining the effects of inflammation, inflammatory mediators and their signaling effectors on calcium and phosphate homeostasis, osteoblast and osteoclast function, and the potential limitations of vitamin D used as an immunomodulator and anabolic hormone in IBD.bone mineral density; Crohn's disease; osteopenia; osteoporosis; ulcerative colitis INFLAMMATORY BOWEL DISEASES (IBDs) represent a group of chronic inflammatory disorders of the intestinal tract that to this date remains idiopathic. More recent basic and clinical research indicates that the chronic inflammatory reaction of the intestinal mucosa is directed against the gut microbiota in individuals with genetic and/or environmental susceptibilities. Disease onset occurs typically during young adulthood (25-35 yr), although ϳ20 -25% of cases are diagnosed during childhood (93). On a clinical basis, two major subtypes of IBD are defined as Crohn's disease (CD), which potentially affects any part of the gastrointestinal tract from the mouth to the anus, and ulcerative colitis (UC), an inflammatory condition limited to the colonic mucosa. However, IBD does not affect just a single organ and should be considered a systemic disease with several extraintestinal manifestations, which occur in a large proportion of IBD patients (60). Osteopenia and osteoporosis are two of the more common extraintestinal symptoms with a general consensus that IBD patients are at a significantly higher risk of developing metabolic bone disease and low bone mineral density (BMD) than the healthy subjects. The relative risk of fractur...

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“…Phex inactivation was postulated to indirectly affect the kidney through bone-released, phosphaturic factors known as phosphatonins. Fibroblast growth factor 23 (FGF23) was one of the leading phosphatonin candidates due to its potent negative effects on renal phosphate reabsorption and its highly elevated expression in X-linked hypophosphatemic ricket patients (6). Although initial studies seemed to confirm this mechanism (7), it was later shown that Phex mutations lead to increased FGF23 expression rather than processing (8), and that FGF23 is cleaved by subtilisin-like proprotein convertases and not PHEX (9).…”

mentioning

confidence: 99%

Cooperative Role of NF-κB and Poly(ADP-ribose) Polymerase 1 (PARP-1) in the TNF-induced Inhibition of PHEX Expression in Osteoblasts

Majewski

Thurston

Ramalingam

et al. 2010

Journal of Biological Chemistry

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Reduced bone mass is a common complication in chronic inflammatory diseases, although the mechanisms are not completely understood. The PHEX gene encodes a zinc endopeptidase expressed in osteoblasts and contributes to bone mineralization. The aim of this study was to determine the molecular mechanism involved in TNF-mediated down-regulation of Phex gene transcription. We demonstrate down-regulation of the Bones have several physiological functions including maintaining organism structure, serving as a hematopoietic niche, calcium and inorganic phosphate reservoir, and regulating and feeding back to other organs via hormone release. To balance both normal serum mineral concentrations and bone mineral density, bones have a dynamic homeostasis that involve boneforming osteoblasts and bone-resorbing osteoclasts. This balance is influenced by hormones, neurotransmitters, and cytokines that act directly on osteoblasts and osteoclasts to affect mineral deposition and release (1).Although normal bone structure is the result of the balance of these two opposite processes, certain genetic disorders can skew this balance leading to low bone mineralization. In vitamin D-resistant, X-linked hypophosphatemic rickets, an inactivating mutation of PHEX 3 (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) leads to hypophosphatemia, aberrant vitamin D levels, high serum alkaline phosphatase, and osteomalacia (2, 3). Although the Phex gene encodes a membrane-bound, zinc metallopeptidase expressed only in osteoblasts and odontoblasts, the effects of its mutation lead to phosphate wasting in the kidney by decreasing the expression and activity of the Na ϩ /P i cotransporter, NaP iIIa (NPT2; SLC24A1) in proximal convoluted tubules (4, 5). Phex inactivation was postulated to indirectly affect the kidney through bone-released, phosphaturic factors known as phosphatonins. Fibroblast growth factor 23 (FGF23) was one of the leading phosphatonin candidates due to its potent negative effects on renal phosphate reabsorption and its highly elevated expression in X-linked hypophosphatemic ricket patients (6). Although initial studies seemed to confirm this mechanism (7), it was later shown that Phex mutations lead to increased FGF23 expression rather than processing (8), and that FGF23 is cleaved by subtilisin-like proprotein convertases and not PHEX (9).In addition to the renal abnormalities in X-linked hypophosphatemic rickets, PHEX inactivation also leads to osteoblast mineralization deficits. This is exemplified by the inability of immortalized osteoblasts from Phex-deficient Hyp mice to mineralize in vitro (10). Although the target(s) of PHEX proteo-* This work was supported, in whole or in part, by National Institutes of Health Grant R37DK033209 (to F. K. G.). Mass spectrometric data acquired by the Arizona Proteomics Consortium was supported by National Institutes of Health Grant ES06694 from the NIEHS to The Southwest Environmental Health Sciences Center, Grant CA023074 from the NCI to the Arizona Cancer ...

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Recent advances in the renal–skeletal–gut axis that controls phosphate homeostasis

Cited by 52 publications

References 81 publications

ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate

ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate

Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases

Cooperative Role of NF-κB and Poly(ADP-ribose) Polymerase 1 (PARP-1) in the TNF-induced Inhibition of PHEX Expression in Osteoblasts

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