insight - Computational Biology - # Testicular microcalcifications and their association with ectopic FGF23 production

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

Q: How do the findings from this study inform potential therapeutic strategies to prevent or manage testicular microcalcifications in both benign and malignant conditions

The findings from this study provide valuable insights into potential therapeutic strategies to prevent or manage testicular microcalcifications in both benign and malignant conditions. One approach could involve targeting the disturbed local phosphate homeostasis observed in the study. By modulating the expression or activity of phosphate transporters such as SLC34A1 and SLC34A2, it may be possible to restore normal phosphate levels in the testis and prevent the formation of microcalcifications. Additionally, interventions aimed at reducing alkaline phosphatase activity, which degrades the mineralization inhibitor pyrophosphate, could be explored to inhibit the osteogenic-like differentiation of testicular cells. Furthermore, strategies to regulate FGF23 signaling, either by promoting glycosylation to stabilize the full-length FGF23 or by inhibiting the cleavage of FGF23 into its C-terminal fragment, may also be considered as potential therapeutic targets.

Q: What other signaling pathways or cellular mechanisms, beyond the ones investigated, might contribute to the osteogenic-like differentiation of testicular cells and the formation of microcalcifications

Beyond the signaling pathways and cellular mechanisms investigated in the study, several other factors may contribute to the osteogenic-like differentiation of testicular cells and the formation of microcalcifications. One potential mechanism could involve the dysregulation of vitamin D metabolism, as alterations in vitamin D metabolizing enzymes have been linked to extra-skeletal calcifications. Moreover, the role of other mineralization inhibitors such as osteopontin and dentin matrix acidic phosphoprotein 1, which were not extensively studied in this research, could play a significant role in preventing mineral deposition in the testis. Additionally, the interaction between inflammatory pathways, oxidative stress, and epigenetic modifications may also influence the differentiation of testicular cells towards a bone-like phenotype and contribute to the development of microcalcifications.

Q: Given the links between testicular microcalcifications, mineral homeostasis, and embryonic stem cell-like properties, how might these insights shed light on the fundamental biology of germ cell development and the origins of testicular germ cell tumors

The insights gained from the study on testicular microcalcifications, mineral homeostasis, and embryonic stem cell-like properties offer valuable implications for understanding the fundamental biology of germ cell development and the origins of testicular germ cell tumors (TGCTs). The findings suggest that the aberrant expression of FGF23 and the dysregulation of phosphate transporters in GCNIS and EC cells may reflect a reprogramming of germ cells towards a more pluripotent state, resembling embryonic stem cells. This highlights the plasticity of germ cells and their potential to undergo osteogenic-like differentiation under specific conditions. Understanding these cellular mechanisms could provide new perspectives on the molecular pathways involved in germ cell development and the transformation of germ cells into malignant tumors. Additionally, the study underscores the importance of maintaining proper mineral homeostasis in the testis for normal germ cell development and the prevention of pathological conditions such as testicular microcalcifications and TGCTs.

Core Concepts

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.

Abstract

The study investigates the etiology of testicular microcalcifications, both benign and malignant, and demonstrates that they occur secondary to changes in gonadal phosphate homeostasis. Key findings include:

Testicular microcalcifications are associated with ectopic expression of the phosphate regulator FGF23, the renal phosphate transporter SLC34A1, and bone markers like BGLAP in germ cells adjacent to the calcifications.
FGF23 is highly expressed in testicular germ cell neoplasia in situ (GCNIS), embryonal carcinoma (EC), and human embryonic stem cells, but not in classical seminoma. The cleaved C-terminal fragment of FGF23 is predominantly produced, which can antagonize the effects of full-length FGF23.
Fgf23 knockout mice exhibit marked calcifications in the epididymis, spermatogenic arrest, and expression of bone markers in germ cells, suggesting FGF23 dysregulation can directly induce mineral disturbances.
Testicular microcalcifications are also observed in hypogonadal mice, androgen receptor knockout mice, and Sertoli cell-ablated mice, indicating that impaired Sertoli cell function and reduced mineralization inhibitors can facilitate osteogenic-like differentiation of testicular cells.
In vitro, calcium and phosphate treatment can induce mineral deposition in a spermatogonial cell line, which is prevented by the mineralization inhibitor pyrophosphate.

The study concludes that testicular microcalcifications arise due to a combination of factors, including disturbed local phosphate homeostasis, decreased Sertoli cell function, reduction of mineralization inhibitors, and aberrant germ cell differentiation, which can drive osteogenic-like changes and hydroxyapatite deposition.

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biorxiv.org

Stats

"Serum levels of calcium and phosphate were significantly higher in Fgf23-/- mice compared to wild-type mice."
"Expression of the phosphate transporters Slc34a1 and Slc34a2, and the bone marker Bglap was altered in the testis of hpg, hpg.SCARKO, and hpg.ARKO mice."
"Calcium and phosphate treatment induced deposition of calcium-phosphate minerals in a spermatogonial cell line, which was prevented by the mineralization inhibitor pyrophosphate."

Quotes

"Testicular microlithiasis in infertile men is associated with an increased risk of testicular germ cell tumors (TGCTs)."
"FGF23, a regulator of phosphate homeostasis, is expressed in testicular germ cell neoplasia in situ (GCNIS), embryonal carcinoma (EC), and human embryonic stem cells."
"Alkaline phosphatase activity was markedly higher in GCNIS tubules compared with normal seminiferous tubules."

Key Insights Distilled From

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

by Boisen,I. M.... at www.biorxiv.org 06-27-2020

https://www.biorxiv.org/content/10.1101/2020.06.25.171355v2

Deeper Inquiries

How do the findings from this study inform potential therapeutic strategies to prevent or manage testicular microcalcifications in both benign and malignant conditions

The findings from this study provide valuable insights into potential therapeutic strategies to prevent or manage testicular microcalcifications in both benign and malignant conditions. One approach could involve targeting the disturbed local phosphate homeostasis observed in the study. By modulating the expression or activity of phosphate transporters such as SLC34A1 and SLC34A2, it may be possible to restore normal phosphate levels in the testis and prevent the formation of microcalcifications. Additionally, interventions aimed at reducing alkaline phosphatase activity, which degrades the mineralization inhibitor pyrophosphate, could be explored to inhibit the osteogenic-like differentiation of testicular cells. Furthermore, strategies to regulate FGF23 signaling, either by promoting glycosylation to stabilize the full-length FGF23 or by inhibiting the cleavage of FGF23 into its C-terminal fragment, may also be considered as potential therapeutic targets.

What other signaling pathways or cellular mechanisms, beyond the ones investigated, might contribute to the osteogenic-like differentiation of testicular cells and the formation of microcalcifications

Beyond the signaling pathways and cellular mechanisms investigated in the study, several other factors may contribute to the osteogenic-like differentiation of testicular cells and the formation of microcalcifications. One potential mechanism could involve the dysregulation of vitamin D metabolism, as alterations in vitamin D metabolizing enzymes have been linked to extra-skeletal calcifications. Moreover, the role of other mineralization inhibitors such as osteopontin and dentin matrix acidic phosphoprotein 1, which were not extensively studied in this research, could play a significant role in preventing mineral deposition in the testis. Additionally, the interaction between inflammatory pathways, oxidative stress, and epigenetic modifications may also influence the differentiation of testicular cells towards a bone-like phenotype and contribute to the development of microcalcifications.

Given the links between testicular microcalcifications, mineral homeostasis, and embryonic stem cell-like properties, how might these insights shed light on the fundamental biology of germ cell development and the origins of testicular germ cell tumors

The insights gained from the study on testicular microcalcifications, mineral homeostasis, and embryonic stem cell-like properties offer valuable implications for understanding the fundamental biology of germ cell development and the origins of testicular germ cell tumors (TGCTs). The findings suggest that the aberrant expression of FGF23 and the dysregulation of phosphate transporters in GCNIS and EC cells may reflect a reprogramming of germ cells towards a more pluripotent state, resembling embryonic stem cells. This highlights the plasticity of germ cells and their potential to undergo osteogenic-like differentiation under specific conditions. Understanding these cellular mechanisms could provide new perspectives on the molecular pathways involved in germ cell development and the transformation of germ cells into malignant tumors. Additionally, the study underscores the importance of maintaining proper mineral homeostasis in the testis for normal germ cell development and the prevention of pathological conditions such as testicular microcalcifications and TGCTs.