
Testicular microcalcifications can arise due to disturbances in local mineral homeostasis, impaired Sertoli cell function, and aberrant germ cell differentiation, which can lead to osteogenic-like transdifferentiation and deposition of hydroxyapatite.


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Testicular microcalcifications consist of hydroxyapatite and have been associated with an increased risk of testicular germ cell tumors (TGCTs) but may also be the result of benign causes such as loss-of-function variants in the phosphate-transporter gene SLC34A2 . Here, we show that fibroblast growth factor 23 (FGF23), a regulator of phosphate homeostasis, is expressed in testicular germ cell neoplasia in situ (GCNIS), embryonal carcinoma (EC), and human embryonic stem cells. FGF23 is not glycosylated in TGCTs and therefore cleaved into a C-terminal fragment which competitively antagonizes full-length FGF23. Here, Fgf23 knockout mice presented with marked calcifications in the epididymis, spermatogenic arrest, and focally germ cells expressing the osteoblast marker bone gamma-carboxyglutamate protein (BGLAP). Moreover, the frequent testicular microcalcifications in mice with no functional androgen receptor and lack of circulating gonadotropins is associated with lower Slc34a2 and higher Slc34a1/Bglap expression compared with wild-type mice. In accordance, human testicular specimens with microcalcifications also have lower SLC34A2 and a subpopulation of germ cells express SLC34A1, BGLAP, and RUNX2 highlighting aberrant local phosphate handling and expression of bone-specific proteins. Mineral disturbance in vitro using calcium or phosphate treatment induced deposition of calcium-phosphate in a spermatogonial cell line and this effect was fully rescued by the mineralization-inhibitor pyrophosphate. In conclusion, testicular microcalcifications may arise secondary to local alterations in mineral homeostasis, which in combination with impaired Sertoli cell function and reduced levels of mineralization-inhibitors due to high alkaline phosphatase activity in GCNIS and TGCTs, facilitate osteogenic-like differentiation of testicular cells and deposition of hydroxyapatite.

### Competing Interest Statement

The authors have declared no competing interest.

Changes in local mineral homeostasis facilitate the formation of benign and malignant testicular microcalcifications

ectopic-production-of-fibroblast-growth-factor-23-induces-mineral-disturbances-osteogenic-transdifferentiation-and-cancer-associated-microcalcifications-in-the-testis


Ectopic Production of Fibroblast Growth Factor 23 Induces Mineral Disturbances, Osteogenic Transdifferentiation, and Cancer-Associated Microcalcifications in the Testis
