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

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• dc.contributor.author Ovejero Crespo, Diana
• dc.contributor.author Michel, Zachary
• dc.contributor.author Cataisson, Christophe
• dc.contributor.author Saikali, Amanda
• dc.contributor.author Galisteo, Rebeca
• dc.contributor.author Yuspa, Stuart H.
• dc.contributor.author Collins, Michael T.
• dc.contributor.author Fernández de Castro, Luis
• dc.date.accessioned 2024-04-19T07:02:52Z
• dc.date.available 2024-04-19T07:02:52Z
• dc.date.issued 2023
• dc.description.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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Ovejero D, Michel Z, Cataisson C, Saikali A, Galisteo R, Yuspa SH, et al. Murine models of HRAS-mediated cutaneous skeletal hypophosphatemia syndrome suggest bone as the FGF23 excess source. J Clin Invest. 2023 May 1;133(9):e159330. DOI: 10.1172/JCI159330
• dc.identifier.doi http://dx.doi.org/10.1172/JCI159330
• dc.identifier.issn 0021-9738
• dc.identifier.uri http://hdl.handle.net/10230/59836
• dc.language.iso eng
• dc.publisher American Society for Clinical Investigation
• dc.relation.ispartof J Clin Invest. 2023 May 1;133(9):e159330
• dc.rights © 2023, Ovejero et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International (CCBY) License (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Bone Biology
• dc.subject.keyword Bone disease
• dc.subject.keyword Endocrinology
• dc.subject.keyword Mouse models
• dc.title Murine models of HRAS-mediated cutaneous skeletal hypophosphatemia syndrome suggest bone as the FGF23 excess source
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion