FGF23 directly inhibits osteoprogenitor differentiation in <i>Dmp1</i> k<i></i>nockout mice

Guillaume Courbon; Dominik Kentrup; Jane Joy Thomas; Xueyan Wang; Hao-Hsuan Tsai; Jadeah J. Spindler; John Von Drasek; Laura Mazudie Ndjonko; Marta Martinez-Calle; Sana Lynch; Lauriane Hivert; Xiaofang Wang; Wenhan Chang; Jian Q. Feng; Valentin David; Aline Martin

doi:10.1172/jci.insight.156850

FGF23 directly inhibits osteoprogenitor differentiation in Dmp1 knockout mice

Guillaume Courbon,¹ Dominik Kentrup,¹ Jane Joy Thomas,¹ Xueyan Wang,¹ Hao-Hsuan Tsai,¹ Jadeah J. Spindler,¹ John Von Drasek,¹ Laura Mazudie Ndjonko,¹ Marta Martinez-Calle,¹ Sana Lynch,¹ Lauriane Hivert,¹ Xiaofang Wang,² Wenhan Chang,³ Jian Q. Feng,⁴ Valentin David,¹ and Aline Martin⁵

Published November 9, 2023 - More info

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Abstract

Fibroblast growth factor 23 (FGF23) is a phosphate (Pi)-regulating hormone produced by bone. Hereditary hypophosphatemic disorders are associated with FGF23 excess, impaired skeletal growth and osteomalacia. Blocking FGF23 became an effective therapeutic strategy in X-linked hypophosphatemia, but testing remains limited in autosomal recessive hypophosphatemic rickets (ARHR). This study investigates the effects of Pi repletion and bone specific deletion of Fgf23 on bone and mineral metabolism in the Dmp1 knockout (Dmp1^KO) mouse model of ARHR.At 12 weeks, Dmp1^KO mice showed increased serum FGF23 and PTH levels, hypophosphatemia, impaired growth, rickets and osteomalacia. Six weeks of dietary Pi supplementation exacerbated FGF23 production, hyperparathyroidism, renal Pi excretion and osteomalacia. In contrast, osteocyte-specific deletion of Fgf23 resulted in a partial correction of FGF23 excess, which was sufficient to fully restore serum Pi levels, but only partially corrected the bone phenotype. In vitro, we show that FGF23 directly impairs osteoprogenitors differentiation and that DMP1 deficiency contributes to impaired mineralization independently of FGF23 or Pi levels.

In conclusion, FGF23-induced hypophosphatemia is only partially responsible for the bone defects observed in Dmp1^KO mice. Our data suggest that combined DMP1 repletion and FGF23 blockade could effectively correct ARHR-associated mineral and bone disorders.

FGF23 directly inhibits osteoprogenitor differentiation in Dmp1 knockout mice

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FGF23 directly inhibits osteoprogenitor differentiation in Dmp1 knockout mice

Guillaume Courbon,1 Dominik Kentrup,1 Jane Joy Thomas,1 Xueyan Wang,1 Hao-Hsuan Tsai,1 Jadeah J. Spindler,1 John Von Drasek,1 Laura Mazudie Ndjonko,1 Marta Martinez-Calle,1 Sana Lynch,1 Lauriane Hivert,1 Xiaofang Wang,2 Wenhan Chang,3 Jian Q. Feng,4 Valentin David,1 and Aline Martin5

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