Promotion of Ccn2 expression and osteoblastic differentiation by actin polymerization, which is induced by laminar fluid flow stress

Abstract

Fluid flow stress (FSS) is a major mechanical stress that induces bone remodeling upon orthodontic tooth movement, whereas CCN family protein 2 (CCN2) is a potent regenerator of bone defects. In this study, we initially evaluated the effect of laminar FSS on Ccn2 expression and investigated its mechanism in osteoblastic MC3T3-E1 cells. The Ccn2 expression was drastically induced by uniform FSS in an intensity dependent manner. Of note, the observed effect was inhibited by a Rho kinase inhibitor Y27632. Moreover, the inhibition of actin polymerization blocked the FSS-induced activation of Ccn2, whereas inducing Factin formation using cytochalasin D and jasplakinolide enhanced Ccn2 expression in the same cells. Finally, Factin formation was found to induce osteoblastic differentiation. In addition, activation of cyclic AMP-dependent kinase, which inhibits Rho signaling, abolished the effect of FSS. Collectively, these findings indicate the critical role of actin polymerization and Rho signaling in CCN2 induction and bone remodeling provoked by FSS.

Cellular and molecular actions of CCN2/CTGF and its role under physiological and pathological conditions

“…Above and below them, transcription factors and post-transcriptional regulatory molecules that are known to directly regulate CCN2 expression [11,24,27,[125][126][127][128] are summarized, respectively. Distinct types of mechanical stresses, such as mechanical stretch Transcriptional and post-transcriptional regulation of the CCN2 gene At the centre, the structures of the CCN2 gene and its mRNA are illustrated.…”

“…and fluid flow shear stress, cause CCN2 expression in different types of the cells [27,28]. Application of low-intensity pulsed ultrasound (LIPUS) is a therapeutic intervention already utilized in orthopaedic clinics, and it also increases CCN2 expression in gingival epithelial cells [29].…”

The CCN family acting throughout the body: recent research developments

“…Hypoxia triggers the production of both CCN1 and CCN2 (63). Of note, a vast number of reports have described the induction of CCN2 by various forms of mechanical stresses in a variety of cells, where signals through Rho family members play a central part (63,64). Recent progress in molecular medicine is revealing the utility of low-intensity pulsed ultrasound (LIPUS) as a physical therapeutic to accelerate tissue regeneration, which is accompanied by enhanced CCN2 production (65).…”

New functional aspects of CCN2 revealed by trans-omic approaches

“…This particular CCN family member plays significant roles in physiological development [7][8][9][10][11][12][13][14][15], wound healing [16], and in the pathological fibrotic remodeling of multiple tissues, organs [17][18][19][20][21][22][23][24][25][26][27][28], and malignancies throughout the body [3,5]. CCN2 is required for the proper development of the olfactory central nervous system [29], pancreas [30], hair follicles [31], and skeletal system [11]; hence, Ccn2-null mice die upon delivery [32,33].…”

“…CCN2 is also known to be involved in multiple steps of orofacial development [34,35]. Specifically, CCN2 is important for skeletal development under the support of complex gene regulatory systems in relevant cells, including osteoblasts, chondrocytes, and osteoclasts [7][8][9][10][11][12][13][14][15]. In this context, a recent report investigated the role of CCN2 in palate development as well [36].…”