Differential regulation of PHEX expression in bone and parathyroid gland by chronic renal insufficiency and 1,25-dihydroxyvitamin D<sub>3</sub>

Brewer, Angela J.; Canaff, Lucie; Hendy, Geoffrey N.; Tenenhouse, Harriet S.

doi:10.1152/ajprenal.00321.2003

Cited by 15 publications

(15 citation statements)

References 46 publications

(53 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4) is similar to the decrease in endogenous PHEX gene expression in UMR-106 cells (Fig. 1) and the in vivo decrease observed in rats (22) and mice, further suggesting similar regulation in vitro and in vivo. Moreover, this observed ϳ50% decrease in PHEX expression by 1,25(OH) 2 D 3 (Figs.…”

Section: Discussionsupporting

confidence: 83%

“…1, B and C). Furthermore, this in vivo decrease in PHEX mRNA expression is in agreement with the approximate 40% decrease in PHEX mRNA and protein expression reported by Brewer et al (22) -106 cells (19, 25). Preliminary experi-ments revealed that the promoterless vector pGL3-Basic (Promega) was itself regulated by 1,25(OH) 2 D 3 in UMR-106 cells (data not shown).…”

Section: Repression Of Phex Expression and Inhibition Of Mineralizatisupporting

confidence: 91%

“…Chronic exposure to 1,25(OH) 2 D 3 significantly represses PHEX transcription in cultured rat osteoblasts (Fig. 1) and mouse calvaria (data not shown), as well as mouse osteoblasts (21) and rat tibia (22). The magnitude of this repression (35-75%) is indicative of pathophysiologic relevance because the disease phenotype of impaired skeletal mineralization in X-linked hypophosphatemia caused by an inactivating PHEX mutation is manifested in heterozygous females with a 50% decrease in PHEX expression (32).…”

Section: Discussionmentioning

confidence: 82%

“…Conversely, PHEX was found to be down-regulated by parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) in UMR-106 osteoblastic cells (20). 1,25(OH) 2 D 3 downregulation of PHEX has been shown at the mRNA and protein levels in both cultured mouse osteoblasts (21) and more recently in 1,25(OH) 2 D 3 -treated rats (22). In primary osteoblasts and MC3T3-E1 cells, 1,25(OH) 2 D 3 -mediated PHEX down-regulation was independent of the mineralization state of the cells (21).…”

mentioning

confidence: 99%

See 3 more Smart Citations

1,25-Dihydroxyvitamin D3 Down-regulation of PHEX Gene Expression Is Mediated by Apparent Repression of a 110 kDa Transfactor That Binds to a Polyadenine Element in the Promoter

Hines¹,

Kolek²,

Jones³

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Bone mineral homeostasis is achieved by the concerted actions of several hormones that control the circulating levels of calcium and phosphate, as well as directly affect osteoblastmediated mineralization and/or osteoclast-driven resorption (1, 2). Thus, skeletal mineral integrity is maintained by the availability of calcium and phosphate ions and by a coupled balance between the activities of osteoblasts and osteoclasts. Prominent among the endocrine factors that regulate bone mineral is the sterol, 1␣-25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), 1 the active renal metabolite of vitamin D 3 (3). 1,25(OH) 2 D 3 functions via its nuclear vitamin D receptor (VDR) to induce intestinal calcium and phosphate absorption, as well as renal phosphate reabsorption, thereby preventing rickets/osteomalacia by ensuring adequate blood concentrations of these ions to facilitate bone mineralization (4, 5). Osteoblasts represent another target for 1,25(OH) 2 D 3 , where the sterol acts via VDR to induce bone remodeling proteins such as osteocalcin (6) and osteopontin (7), as well as the receptor activator of NF-B ligand (RANKL), which is a paracrine signal for osteoclastogenesis (8). Therefore, as a calcemic and phosphatemic hormone, 1,25(OH) 2 D 3 operates directly to resorb/remodel bone, and we show in the present communication that this sterol paradoxically also inhibits mineralization by cultured osteoblasts. The mechanism whereby 1,25(OH) 2 D 3 limits bone mineralization is herein characterized as the apparent up-regulation of a novel phosphaturic peptide(s), termed phosphatonin, via a repression in osteoblasts of the expression of a gene encoding a neutral endopeptidase PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) that is hypothesized to normally inactivate phosphatonin by proteolysis.Phosphatonin, an uncharacterized phosphaturic hormone that may include in part FGF23 (9), is an inhibitor of osteoblastic mineralization, which also blocks renal 25-OH-vitamin D 3 bioactivation to 1,25(OH) 2 D 3 , and elicits hypophosphatemia by repressing the renal type IIa sodium phosphate cotransporter (NaP i -IIa) (10). The PHEX gene encodes an endopeptidase that is predominantly expressed in osteoblasts and osteocytes (11,12). Phenotypically, inactivating mutations in the PHEX gene results in vitamin D-resistant, X-linked hypophosphatemic rickets (X-linked hypophosphatemia; XLH) (11). This familial disorder manifests as hypophosphatemia, low circulat-

show abstract

Section: Discussionsupporting

confidence: 83%

Section: Repression Of Phex Expression and Inhibition Of Mineralizatisupporting

confidence: 91%

Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

See 2 more Smart Citations

1,25-Dihydroxyvitamin D3 Down-regulation of PHEX Gene Expression Is Mediated by Apparent Repression of a 110 kDa Transfactor That Binds to a Polyadenine Element in the Promoter

Hines¹,

Kolek²,

Jones³

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…PHEX also plays a major role in renal phosphate handling but is not expressed in the kidney, suggesting the secondary involvement of a circulating systemic factor. Recent studies confirm that PHEX expression in brain and PTH glands may also play a key role in phosphate homeostasis (Blydt-Hansen et al, 1999;Brewer et al, 2003).…”

Section: (2) Phex: a Protease And Ligand?mentioning

confidence: 90%

The Wrickkened Pathways of FGF23, MEPE and PHEX

Rowe

2004

Critical Reviews in Oral Biology & Medicine

140

127

View full text Add to dashboard Cite

ABSTRACT:The last 350 years since the publication of the first medical monograph on rickets (old English term wrickken) (Glisson et al., 1651) have seen spectacular advances in our understanding of mineral-homeostasis. Seminal and exciting discoveries have revealed the roles of PTH, vitamin D, and calcitonin in regulating calcium and phosphate, and maintaining healthy teeth and skeleton. However, it is clear that the PTH/Vitamin D axis does not account for the entire picture, and a new bone-renal metabolic milieu has emerged, implicating a novel set of matrix proteins, hormones, and Zn-metallopeptidases. The primary defects in X-linked hypophosphatemic rickets (HYP) and autosomal-dominant hypophosphatemic rickets (ADHR) are now identified as inactivating mutations in a Zn-metalloendopeptidase (PHEX) and activating mutations in fibroblast-growthfactor-23 (FGF23), respectively. In oncogenic hypophosphatemic osteomalacia (OHO), several tumor-expressed proteins (MEPE, FGF23, and FRP-4) have emerged as candidate mediators of the bone-renal pathophysiology. This has stimulated the proposal of a global model that takes into account the remarkable similarities between the inherited diseases (HYP and ADHR) and the tumor-acquired disease OHO. In HYP, loss of PHEX function is proposed to result in an increase in uncleaved full-length FGF23 and/or inappropriate processing of MEPE. In ADHR, a mutation in FGF23 results in resistance to proteolysis by PHEX or other proteases and an increase in half-life of full-length phosphaturic FGF23. In OHO, over-expression of FGF23 and/or MEPE is proposed to result in abnormal renal-phosphate handling and mineralization. Although this model is attractive, many questions remain unanswered, suggesting a more complex picture. The following review will present a global hypothesis that attempts to explain the experimental and clinical observations in HYP, ADHR, and OHO, plus diverse mouse models that include the MEPE null mutant, HYP-PHEX transgenic mouse, and MEPE-PHEX double-null-mutant.

show abstract

Gene profiling involved in fate determination of salivary gland type in mouse embryogenesis

et al. 2018

View full text Add to dashboard Cite

Salivary gland (SG) development involves dynamic epithelial-mesenchymal interactions resulting in the formation of highly branched epithelial structures that produce and secrete saliva. The SG epithelium differentiates into saliva-producing terminal buds, i.e., acini, and transporting ducts. Most studies on the salivary gland have focused on branching morphogenesis; however, acinar cell differentiation underlying the determination of serous or mucous salivary glands is unclear. The objective of this study was to identify the mesenchymal signaling molecules involved in the epithelial differentiation of the salivary gland type as serous or mucous. Salivary glands undergoing stage-specific development, including the parotid gland (PG) and the sublingual gland (SLG) at embryonic day 14.5 (E14.5) were dissected. The glands were treated with dispase II to separate the epithelium and the mesenchyme. RNA from mesenchyme was processed for microarray analysis. Thereafter, microarray data were analyzed to identify putative candidate molecules involved in salivary gland differentiation and confirmed via quantitative reverse transcription polymerase chain reaction. The microarray analysis revealed the expression of 31,873 genes in the PG and SLG mesenchyme. Of the expressed genes 21,026 genes were found to be equally expressed (Fold change 1.000) in both PG and SLG mesenchyme. The numbers of genes expressed over onefold in the PG and SLG mesenchyme were found to be 5247 and 5600 respectively. On limiting the fold-change cut off value over 1.5 folds, only 214 and 137 genes were expressed over 1.5 folds in the PG and the SLG mesenchyme respectively. Our findings suggest that differential expression patterns of the mesenchymal signaling molecules are involved in fate determination of the salivary acinar cell types during mouse embryogenesis. In the near future, functional evaluation of the candidate genes will be performed using gain- and loss-of-function mutation studies during in vitro organ cultivation.

show abstract

Differential regulation of PHEX expression in bone and parathyroid gland by chronic renal insufficiency and 1,25-dihydroxyvitamin D₃

Cited by 15 publications

References 46 publications

1,25-Dihydroxyvitamin D3 Down-regulation of PHEX Gene Expression Is Mediated by Apparent Repression of a 110 kDa Transfactor That Binds to a Polyadenine Element in the Promoter

1,25-Dihydroxyvitamin D3 Down-regulation of PHEX Gene Expression Is Mediated by Apparent Repression of a 110 kDa Transfactor That Binds to a Polyadenine Element in the Promoter

The Wrickkened Pathways of FGF23, MEPE and PHEX

Gene profiling involved in fate determination of salivary gland type in mouse embryogenesis

Contact Info

Product

Resources

About

Differential regulation of PHEX expression in bone and parathyroid gland by chronic renal insufficiency and 1,25-dihydroxyvitamin D3

Cited by 15 publications

References 46 publications

1,25-Dihydroxyvitamin D3 Down-regulation of PHEX Gene Expression Is Mediated by Apparent Repression of a 110 kDa Transfactor That Binds to a Polyadenine Element in the Promoter

1,25-Dihydroxyvitamin D3 Down-regulation of PHEX Gene Expression Is Mediated by Apparent Repression of a 110 kDa Transfactor That Binds to a Polyadenine Element in the Promoter

The Wrickkened Pathways of FGF23, MEPE and PHEX

Gene profiling involved in fate determination of salivary gland type in mouse embryogenesis

Contact Info

Product

Resources

About

Differential regulation of PHEX expression in bone and parathyroid gland by chronic renal insufficiency and 1,25-dihydroxyvitamin D₃