Abstract
Connective tissue growth factor (CTGF), which is also called CCN2, is a secreted matricellular protein. CTGF regulates various important cellular functions by interacting with multiple molecules in the microenvironment. In the ovary, CTGF is mainly expressed in granulosa cells and involved in the regulation of follicular development, ovulation and luteinization. TGF-β1 has been shown to up-regulate CTGF expression in rat and hen granulosa cells. However, the underlying molecular mechanisms of this up-regulation remain undefined. More importantly, whether the stimulatory effect of TGF-β1 on CTGF expression can be observed in human granulosa cells remains unknown. In the present study, our results demonstrated that TGF-β1 treatment up-regulates CTGF expression in both immortalized human granulosa cells and primary human granulosa cells. Using a siRNA-mediated knockdown approach and a pharmacological inhibitor, we demonstrated that the inhibition of Smad2, Smad3 or ERK1/2 attenuates the TGF-β1-induced up-regulation of CTGF. This study provides important insights into the molecular mechanisms that mediate TGF-β1-up-regulated CTGF expression in human granulosa cells.
Highlights
Connective tissue growth factor (CTGF) is a secreted protein that belongs to the CCN family, which consists of the following six members: cysteine-rich protein 61 (CYR61/CCN1), CTGF (CCN2), nephroblastoma overexpressed gene (NOV/CCN3), Wnt-inducible secreted protein1 (WISP-1/CCN4), WISP-2 (CCN5) and WISP-3 (CCN6) [1]
Our previously established SVOG cells were used to examine the effect of TGF-β1 on CTGF expression in human granulosa cells [26]
All bands were affected by the TGF-β1 and CTGF Small interfering RNA (siRNA) treatments, which confirmed the specificity of the CTGF antibody that was used in the present study
Summary
Connective tissue growth factor (CTGF) is a secreted protein that belongs to the CCN family, which consists of the following six members: cysteine-rich protein 61 (CYR61/CCN1), CTGF (CCN2), nephroblastoma overexpressed gene (NOV/CCN3), Wnt-inducible secreted protein (WISP-1/CCN4), WISP-2 (CCN5) and WISP-3 (CCN6) [1]. The CCN family of proteins, which are known as matricellular proteins, primarily act as modulators that regulate multiple cellular functions in response to various environmental stimuli [2]. CCN family members have been shown to regulate cell proliferation, apoptosis, migration, differentiation. TGF-β1 Up-Regulates CTGF in Human Granulosa Cells and extracellular matrix remodeling [3]. CTGF, which was originally identified as a growth factor-inducible immediate early gene in mouse fibroblasts and in human vascular endothelial cells, is the most studied member of this family [4, 5]. CTGF is expressed in multiple cell types and plays important regulatory roles in female reproductive organs [6, 7]
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