Transforming growth factor-β1 up-regulates connexin43 expression in osteocytes via canonical Smad-dependent signaling pathway.

Wenjing Liu,Xuedong Zhou,Yujia Cui,Linyi Cai,Jianxun Sun,Jing Xie

doi:10.1042/bsr20181678

Abstract

Connexin 43 (Cx43)-mediated gap junctional intercellular communication (GJIC) has been shown to be important in regulating multiple functions of bone cells. Transforming growth factor-β1 (TGF-β1) exhibited controversial effects on the expression of Cx43 in different cell types. To date, the effect of TGF-β1 on the Cx43 expression of osteocytes is still unknown. In the present study, we detected the expression of TGF-β1 in osteocytes and bone tissue, and then used recombinant mouse TGF-β1 to elucidate its effect on gap junctions (GJs) of osteocytes. Our data indicated that TGF-β1 up-regulated both mRNA and protein expression of Cx43 in osteocytes. Together with down-regulation of Cx43 expression after being treated with TGF-β type I receptor inhibitor Repsox, we deduced that TGF-β1 can positively regulate Cx43 expression in osteocytes. Thus we next focussed on the downstream signals of TGF-β and found that TGF-β1-mediated smads, Smad3 and Smad4, to translocate into nucleus. These translocated signal proteins bind to the promoter of Gja1 which was responsible for the changed expression of Cx43. The present study provides evidence that TGF-β1 can enhance GJIC between osteocytes through up-regulating Cx43 expression and the underlying mechanism involved in the activation of Smad-dependent pathway.

Highlights

Osteocytes, which make up >95% of bone cells, had been considered a relatively inactive cell for many years as there has been a lack of clear understanding about their functions in the skeleton
We investigated the expression of transforming growth factor (TGF)-β superfamily members and their receptors in both osteocytes and bone tissue by quantitative real-time PCR (Figure 1)
The results showed that Transforming growth factor-β1 (TGF-β1) exhibited the highest expression in osteocytes amongst TGF-β superfamily members

Summary

Introduction

Osteocytes, which make up >95% of bone cells, had been considered a relatively inactive cell for many years as there has been a lack of clear understanding about their functions in the skeleton. It has been revealed that osteocytes reside in the mineralized bone matrix, they connect to cells on the bone surface and to the vasculature through stretching their dendritic processes [1] This cell-to-cell and cell-to-matrix communication is mediated by gap junctions (GJs) and hemi-channels. Cx43-mediated gap junctional intercellular communication (GJIC) serves important roles in the skeletal network, including participation in mechanotransduction [9], endocortical bone resorption and bone remodeling, regulating osteocyte survival, and so on [10]. This vital protein can be affected by some cytokines, such as interleukin, tumor necrosis factor-α (TNF-α), and transforming growth factor-β [11]

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Discussion

Conclusion