Next Article in Journal
Lack of Fas/FasL Does Not Protect from Latent Herpes Simplex 1 Infection but Decreases Virus-Induced Neurodegeneration
Previous Article in Journal
Astrocyte-Mediated Plasticity: Multi-Scale Mechanisms Linking Synaptic Dynamics to Learning and Memory
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 14
Issue 24
10.3390/cells14241937
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

ucOCN Promotes Testosterone Synthesis via the PKA-MAPK/ERK-CREB Signaling Pathway in Porcine Leydig Cells

by
Guang Yang
1,2,3,†,
Han Liu
1,2,3,†,
Zhibao Yin
1,2,3,
Lihua Zhao
1,2,3,
Yanglin Chen
4,5,6,
Yiqing Li
1,2,3,
Linxin Cheng
1,2,3,
Junjun Ma
1,2,3,
Jinbo Yu
1,2,3,
Yu Zhang
1,2,3,
Xihe Li
4,5,6,* and
Rongfeng Li
1,2,3,6,*
1
Jiangsu Provincial Key Laboratory of Biological Therapy for Organ Failure, Nanjing Medical University, Nanjing 211166, China
2
State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China
3
Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, China
4
The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Science, Inner Mongolia University, Hohhot 010020, China
5
National Center of Technology Innovation for Dairy, Hohhot 010020, China
6
Inner Mongolia Saikexing Institute of Breeding and Reproductive Biotechnology in Domestic Animal, Hohhot 011517, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2025, 14(24), 1937; https://doi.org/10.3390/cells14241937
Submission received: 4 November 2025 / Revised: 30 November 2025 / Accepted: 3 December 2025 / Published: 5 December 2025
(This article belongs to the Section Reproductive Cells and Development)
Versions Notes

Abstract

Bone health might be closely associated with male fertility, yet the molecular pathways remain poorly characterized. We demonstrate that undercarboxylated osteocalcin (ucOCN), a bone-derived hormone, initiates a signaling cascade that stimulates testosterone biosynthesis in porcine Leydig cells. Mechanistically, ucOCN binding to membrane receptor GPRC6A elevates intracellular cAMP levels and sequentially activates PKA, MEK, and ERK. ERK translocates to the nucleus and phosphorylates the transcription factor CREB. Activated CREB binds directly to promoter regions of the key steroidogenic genes and boosts testosterone production. The genetic or pharmacological inhibition of GPRC6A, PKA, MEK, or ERK signaling disrupts CREB activation and abolishes both steroidogenic gene expression and testosterone synthesis. Crucially, the phospho-switch S298 as a previously unrecognized phosphorylation site through which MEK regulates osteocalcin (OCN) signaling was identified. Collectively, our results indicate that ucOCN interacts with GPRC6A to promote testosterone synthesis in Leydig cells via the PKA-MAPK/ERK-CREB pathway. The above findings elucidate a fundamental endocrine axis between bone and the male reproductive system, offering novel mechanistic insights and potential therapeutic strategies for improving male fertility.
Keywords: porcine Leydig cells; ucOCN; MEK S298 phospho-switch; PKA-MAPK/ERK-CREB signaling pathway; steroidogenic gene promoter activation porcine Leydig cells; ucOCN; MEK S298 phospho-switch; PKA-MAPK/ERK-CREB signaling pathway; steroidogenic gene promoter activation

Share and Cite

MDPI and ACS Style

Yang, G.; Liu, H.; Yin, Z.; Zhao, L.; Chen, Y.; Li, Y.; Cheng, L.; Ma, J.; Yu, J.; Zhang, Y.; et al. ucOCN Promotes Testosterone Synthesis via the PKA-MAPK/ERK-CREB Signaling Pathway in Porcine Leydig Cells. Cells 2025, 14, 1937. https://doi.org/10.3390/cells14241937

AMA Style

Yang G, Liu H, Yin Z, Zhao L, Chen Y, Li Y, Cheng L, Ma J, Yu J, Zhang Y, et al. ucOCN Promotes Testosterone Synthesis via the PKA-MAPK/ERK-CREB Signaling Pathway in Porcine Leydig Cells. Cells. 2025; 14(24):1937. https://doi.org/10.3390/cells14241937

Chicago/Turabian Style

Yang, Guang, Han Liu, Zhibao Yin, Lihua Zhao, Yanglin Chen, Yiqing Li, Linxin Cheng, Junjun Ma, Jinbo Yu, Yu Zhang, and et al. 2025. "ucOCN Promotes Testosterone Synthesis via the PKA-MAPK/ERK-CREB Signaling Pathway in Porcine Leydig Cells" Cells 14, no. 24: 1937. https://doi.org/10.3390/cells14241937

APA Style

Yang, G., Liu, H., Yin, Z., Zhao, L., Chen, Y., Li, Y., Cheng, L., Ma, J., Yu, J., Zhang, Y., Li, X., & Li, R. (2025). ucOCN Promotes Testosterone Synthesis via the PKA-MAPK/ERK-CREB Signaling Pathway in Porcine Leydig Cells. Cells, 14(24), 1937. https://doi.org/10.3390/cells14241937

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop