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The wrickkened pathways of FGF23, MEPE and PHEX.
Crit Rev Oral Biol Med. 2004 Sep 01; 15(5):264-81.CR

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-growth-factor-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.

Authors+Show Affiliations

Department of Periodontics, The University of Texas Health Science Center at San Antonio, Mail Code 7894, 7703 Floyd Curl Drive, Room 3.579U, San Antonio, TX 78229-3900, USA. rowep@uthscsa.edu

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

Language

eng

PubMed ID

15470265

Citation

Rowe, Peter S N.. "The Wrickkened Pathways of FGF23, MEPE and PHEX." Critical Reviews in Oral Biology and Medicine : an Official Publication of the American Association of Oral Biologists, vol. 15, no. 5, 2004, pp. 264-81.
Rowe PS. The wrickkened pathways of FGF23, MEPE and PHEX. Crit Rev Oral Biol Med. 2004;15(5):264-81.
Rowe, P. S. (2004). The wrickkened pathways of FGF23, MEPE and PHEX. Critical Reviews in Oral Biology and Medicine : an Official Publication of the American Association of Oral Biologists, 15(5), 264-81.
Rowe PS. The Wrickkened Pathways of FGF23, MEPE and PHEX. Crit Rev Oral Biol Med. 2004 Sep 1;15(5):264-81. PubMed PMID: 15470265.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The wrickkened pathways of FGF23, MEPE and PHEX. A1 - Rowe,Peter S N, Y1 - 2004/09/01/ PY - 2004/10/8/pubmed PY - 2005/2/24/medline PY - 2004/10/8/entrez SP - 264 EP - 81 JF - Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists JO - Crit Rev Oral Biol Med VL - 15 IS - 5 N2 - 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-growth-factor-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. SN - 1544-1113 UR - https://www.unboundmedicine.com/medline/citation/15470265/The_wrickkened_pathways_of_FGF23_MEPE_and_PHEX_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/15470265/ DB - PRIME DP - Unbound Medicine ER -