Murine models of HRAS-mediated cutaneous skeletal hypophosphatemia syndrome suggest bone as the FGF23 excess source
Diana Ovejero, … , Michael T. Collins, Luis F. de Castro
Diana Ovejero, … , Michael T. Collins, Luis F. de Castro
Published March 21, 2023
Citation Information: J Clin Invest. 2023;133(9):e159330. https://doi.org/10.1172/JCI159330.
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Research Article Bone biology Endocrinology

Murine models of HRAS-mediated cutaneous skeletal hypophosphatemia syndrome suggest bone as the FGF23 excess source

Abstract

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a mosaic RASopathy characterized by the association of dysplastic skeletal lesions, congenital skin nevi of epidermal and/or melanocytic origin, and FGF23-mediated hypophosphatemia. The primary physiological source of circulating FGF23 is bone cells. However, several reports have suggested skin lesions as the source of excess FGF23 in CSHS. Consequently, without convincing evidence of efficacy, many patients with CSHS have undergone painful removal of cutaneous lesions in an effort to normalize blood phosphate levels. This study aims to elucidate whether the source of FGF23 excess in CSHS is RAS mutation–bearing bone or skin lesions. Toward this end, we analyzed the expression and activity of Fgf23 in two mouse models expressing similar HRAS/Hras activating mutations in a mosaic-like fashion in either bone or epidermal tissue. We found that HRAS hyperactivity in bone, not skin, caused excess of bioactive intact FGF23, hypophosphatemia, and osteomalacia. Our findings support RAS-mutated dysplastic bone as the primary source of physiologically active FGF23 excess in patients with CSHS. This evidence informs the care of patients with CSHS, arguing against the practice of nevi removal to decrease circulating, physiologically active FGF23.

Authors

Diana Ovejero, Zachary Michel, Christophe Cataisson, Amanda Saikali, Rebeca Galisteo, Stuart H. Yuspa, Michael T. Collins, Luis F. de Castro

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Figure 5

Both bone mouse models had systemic inflammation.

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Both bone mouse models had systemic inflammation. Fgf23 mRNA expression ...
Fgf23 mRNA expression was markedly increased in HRASG12V-expressing bone and detectable in some Epi HrasG12R grafts and skin control samples. (A) Plasmatic levels of SAP, an acute-phase inflammatory marker (n = 6–24). (B) qPCR showing Fgf23 versus Gapdh expression in tibial cortical bone from bone HRASG12V mice and their littermate controls; affected skin from Epi HrasG12R mice and normal skin from their littermate controls; and nontransgene expressing vertebrae from both mouse models. Epidermal mouse sample individual data points are represented by white circles; bone mouse sample data points are represented by black circles; averages are represented as bars. Average Fgf23/Gapdh expression in vertebrae from each model’s control group was used to normalize data (n = 6–10). (C) Total FGF23 and (D) intact FGF23 levels in media conditioned by 48-hour incubation of cortical bone tissue from control and HRASG12V-expressing tibiae as well as unaffected skin or skin grafted with WT or HrasG12R-expressing keratinocytes from both mouse models. FGF23 levels are normalized by total protein content in the media in pg of FGF23 per g of total protein (n = 6). *P < 0.05; **P < 0.01; ****P < 0.0001 versus controls. #P < 0.05; ###P < 0.001 versus Epi HrasG12R. Kruskal-Wallis test with Dunn’s adjustment for multiple comparisons (A); 1-way ANOVA with Bonferroni’s adjustment for multiple comparisons was used for the skin samples (C and D); 2-tailed Student’s t test was used for all other comparisons.