Matrix extracellular phosphoglycoprotein (MEPE) correlates with serum phosphorus prior to and during octreotide treatment and following excisional surgery in hypophosphatemic linear sebaceous nevus syndrome

Abstract

How to cite this article: Hoffman WH, Jain A, Chen H, Fedarko NS. 2008. Matrix extracellular phosphoglycoprotein (MEPE) correlates with serum phosphorus prior to and during octreotide treatment and following excisional surgery in hypophosphatemic linear sebaceous nevus syndrome. Am J Med Genet Part A 146A:2164-2168. To the Editor:Hereditary and acquired forms of hypophosphatemia result in metabolic bone disease with significant degrees of disability in children, adolescents and adults. Linear sebaceous nevus syndrome (LSNS) is a rare sporadic congenital phakomatosis of unknown etiology with a variable phenotype that includes hypophosphatemia [Carey et al., 1986].We have previously reported on a patient with LSNS and hypophosphatemia where the plasma phosphatonin, fibroblast growth factor-23 (FGF-23), was inversely related to the serum phosphorous prior to and after treatment with octreotide and excision surgery [Hoffman et al., 2005]. We now extend that observation by reporting on the positive correlation between serum phosphorus and matrix extracellular phosphoglycoprotein (MEPE), a downstream member of phosphate homeostasis and mineralization.Briefly, the patient, a 7-year-old boy of Korean ancestry with LSNS (which followed Blaschko's lines and involved the left side of his face, trunk, upper and lower extremities and epidermal nevi of the limbus) began treatment for hypophosphatemic rickets with phosphate and calcitriol for vitamin Dresistant rickets. Octreotide (Sandostatin LAR) was added to the phosphate and calcitriol therapy when he was 16 years of age, due to increasing musculoskeletal symptoms and frequent stress fractures and persistent hypophosphatemia [Hoffman et al., 2005]. Further details of the treatment protocol are given in the legend for Figure 1. The competitive enzyme-linked immunosorbent (ELISA) assays for MEPE were performed as previously described [Jain et al., 2004]. The antibody employed in the competitive ELISA (LF-155, a kind gift of Dr. L.W. Fisher, N.I.D.C.R., N.I.H.) was raised against exon 4, the last coding exon of human MEPE, and was affinitypurified using recombinantly expressed protein. The assay entails an anion exchange column chromatography step to clean up the sample and detects intact, full length MEPE. The bioactive acidic serineaspartate-rich MEPE (ASARM) peptide was assayed by a competitive ELISA specific for ASARM-peptide epitopes [Bresler et al., 2004] in the laboratory of Dr. P Rowe. Associations between MEPE and phosphorus were analyzed by Pearson regression analysis.FGF-23 decreased within 1 month following the first injection of depot octreotide, was suppressed during the 4 months of injections, and remained in the normal range over the following 6 months. After a further decrease following surgery, FGF-23

Regulation and Function of the FGF23/Klotho Endocrine Pathways

“…174800) and two sporadic/acquired disorders, including tumor-induced osteomalacia (TIO) and hypophosphatemic linear nevus sebaceous syndrome (OMIM no. 163200) (65), also result in elevated FGF23 and hypophosphatemia. GNAS1 leads to variable increase in FGF23 that is limited to fibrotic lesions of bone, whereas TIO is produced from mesenchymal derived tumors and linear nevus sebaceous syndrome (66) appears to have increased bone remodeling as a potential source of FGF23 (TABLE 1).…”

Regulation of Bone−Renal Mineral and Energy Metabolism: The PHEX, FGF23, DMP1, MEPE ASARM Pathway

“…24,26,31,34–37,136 The pathophysiological ASARM pathway inhibits renal phosphate uptake independent of FGF23 and exacerbates the FGF23-induced hypophosphate-mia found in familial HYP, ARHR and ADHR. 21,34 ASARM peptides are acidic, phosphorylated and highly charged, with low isolectric points (pI).…”

The chicken or the egg: PHEX, FGF23 and SIBLINGs unscrambled

“…( A ); specifically, accumulation of ASARM peptides inhibits mineralization and ( B ); coordinately inhibits Na+ dependent phosphate uptake in the kidney as shown in vitro and in vivo 32, 35, 41–45, 145 . The pathophysiological ASARM-pathway inhibits renal phosphate uptake independent of FGF23 and exacerbates the FGF23 induced hypophosphatemia found in familial XLH, ARHR and ADHR 10, 42 .…”

“…(A) Specifically, accumulation of ASARM peptides inhibits mineralization and (B) coordinately inhibits Na + -dependent phosphate uptake in the kidney as shown in vitro and in vivo. 32,35,[41][42][43][44][45]145 The pathophysiological ASARM pathway inhibits renal phosphate uptake independent of FGF23 and exacerbates the FGF23-induced hypophosphatemia found in familial XLH, ARHR and ADHR. 10,42 ASARM peptides are acidic, phosphorylated, highly charged, with low pIs and are extraordinarily resistant to a wide range of proteases (see references; 10,32,38 also unpublished observations) and have physicochemical similarities to bisphosphonates, phosphonoformic acid (PFA) and phosphonoacetic acid (PAA).…”