CCN4/WISP-1 positively regulates chondrogenesis by controlling TGF-β3 function

Abstract

The CCN family of proteins plays important roles in development and homeostasis of bone and cartilage. To understand the role of CCN4 in chondrogenesis, human bone marrow stromal cells (hBMSCs) were transduced with CCN4 adenovirus (adCCN4) or siRNA to CCN4 (siCCN4) in the presence or absence of transforming growth factor-β3 (TGF-β3). Overexpression of CCN4 enhanced TGF-β3-induced SMAD2/3 phosphorylation and chondrogenesis of hBMSCs in an in vitro assay using a micromass culture model. On the other hand, knockdown of CCN4 inhibited the TGF-β3-induced SMAD2/3 phosphorylation and synthesis of cartilage matrix in micromass cultures of hBMSCs. Immunoprecipitation–western blot analysis revealed that CCN4 bound to TGF-β3 and regulated the ability of TGF-β3 to bind to hBMSCs. In vivo analysis confirmed there was a significant decrease in the gene expression levels of chondrocyte markers in cartilage samples from Ccn4-knock out (KO) mice, compared to those from wild type (WT) control. In order to investigate the regenerative properties of the articular cartilage in Ccn4-KO mice, articular cartilage defects were surgically performed in the knee joints of young mice, and the results showed that the cartilage was partially repaired in WT mice, but not in Ccn4-KO mice. In conclusion, these results show, for the first time, that CCN4 has a positive influence on chondrogenic differentiation by modulating the effects of TGF-β3.

CCN4/WISP1 controls cutaneous wound healing by modulating proliferation, migration and ECM expression in dermal fibroblasts via α5β1 and TNFα

“…Previous studies showed that CCN1 and CCN2 regulate dermal fibroblast proliferation in vitro and are important in wound healing in vivo [9, 11–15]. While we and others showed that CCN4 is important in the musculoskeletal system where it regulates both osteogenesis and chondrogenesis [16–18], the role of CCN4 in cutaneous wound healing remains unclear.…”

“…StelthTM RNAi negative control high GC Duplex (Life Technologies) was used as the negative control. For the overexpression of the CCN4 gene, hADFs were transfected with adenovirus expressing human CCN4 (adCCN4) as reported previously [16–18]. Adenovirus with a CMV promoter minus the CCN4 coding sequence (adCMV) was used as the negative control.…”

Post-traumatic osteoarthritis development is not modified by postnatal chondrocyte deletion of Ccn2

“…The effects of Ccn2 deletion on chondrogenesis and OA development are similar to those of other CCN members. Indeed, deletion of Ccn4 , also known as Wisp1 , was shown to promote chondrogenesis and cartilage repair ( Yoshioka et al, 2016 ), whereas it can also promote OA development ( van den Bosch et al, 2017 ). The latter was linked to differential effects of Ccn4 deletion on OA tissues, with synovial tissue being more responsive to Ccn4 deletion than cartilage in OA joints.…”

WNT1 Inducible Signaling Pathway Protein 1 (WISP1) stimulates melanoma cell invasion and metastasis by promoting epithelial – mesenchymal transition

“…Clarifying the in vivo relations between aberrant Wnt/β-catenin signaling and functional implications of WISP1 signaling may help explain the prevalence of early metastatic dissemination in melanoma. As a secreted signaling molecule, WISP1 connects intrinsic cell signaling pathways with biological cues released into the tissue microenvironment to restore homeostasis following tissue damage (45)(46)(47) and to sustain a mesenchymal stem cell niche (48). While these studies focus on bone and cartilage homeostasis, the expression of WISP1 by normal melanocytes and dermal fibroblasts ( Fig.…”