Krüppel-Like Factor 2 Regulates Degradation of Type II Collagen by Suppressing the Expression of Matrix Metalloproteinase (MMP)-13

Abstract

Background/Aims: Krüppel-like factor 2 (KLF2) plays an essential role in the inhibition of endothelial cell and macrophage activation during the inflammatory process. However, the roles of KLF2 in chondrocytes and the pathological progression of osteoarthritis (OA) remain unknown. The aim of this study was to investigate the function of KLF2 in the inhibition of cartilage matrix destruction in chondrocytes. Methods: RT-PCR and western blot analysis was used to determine the expression of KLF2 in human chondrocytes. Luciferase assay, ELISA assay and MMP-13 enzymatic activity assays were used to investigate the effects of KLF2 in regulating MMP-13 expression. Western blot analysis was used to examine the effects of KLF2 in suppressing degradation of type Ⅱ collagen. Results: KLF2 is expressed in primary chondrocytes and is downregulated in OA chondrocytes. Expression of KLF2 in primary chondrocytes was reduced in response to IL-1β. Overexpression of KLF2 robustly inhibited IL-1β-induced MMP-13 expression. Conversely, knockdown of KLF2 markedly exacerbated MMP-13 expression. Mechanistically, KLF2 could suppress the activation of MMP-13 promoter. However, knockdown of KLF2 could promote the activation of MMP-13 promoter. Importantly, overexpression of KLF2 ameliorated the degradation of type Ⅱ collagen while silencing of KLF2 exacerbated the degradation of type Ⅱ collagen induced by IL-1β. Conclusions: KLF2 may be a potential therapeutic target for OA treatment.

A whole-genome transcriptome analysis of articular chondrocytes in secondary osteoarthritis of the hip

“…Considering these facts, KLF2 can be a potential regulator of expression of MMP s in chondrocytes, and related to OA onset and/or progression. KLF2 expression was reportedly downregulated in human OA chondrocytes contrary to our results, wherein KLF2 upregulation suppressed MMP13 expression and ameliorated type II collagen degradation [ 38 ]. Although no information was provided on OA staging in Yuan’s report, this discrepancy could be a result of the difference in OA grade, as expression patterns of specific genes in chondrocytes depend on the stage of OA [ 39 ].…”

Epigenetic silencing of KLF2 by long non-coding RNA SNHG1 inhibits periodontal ligament stem cell osteogenesis differentiation

“…It has been reported that KLF2 regulates cellular growth and differentiation [35]. KLF2 was involved in degradation of type II collagen, a primary component of the extracellular matrix in articular cartilage, through inhibiting matrix metalloproteinase-13 expression [36]. Interestingly, KLF2 was reported to be significantly increased during the osteoblastic differentiation process and KLF2 could promote the expression of the osteoblastic differentiation marker genes Alp, Osx, and Ocn and stimulate mineralization by enhancing the expression of and interacting with Runx2 [37].…”

Circ_0136474 and MMP‐13 suppressed cell proliferation by competitive binding to miR‐127‐5p in osteoarthritis

“…Matrix metalloproteinases (MMPs) family function in irreversible matrix degradation and subsequent joint destruction in OA . Previous reports showed that Interleukin‐1β (IL‐1β) and tumour necrosis factor‐α (TNF‐α) are two most potent catabolic factors that increase the production of inflammatory mediators and the expression of MMPs in chondrocytes .…”

“…12 Matrix metalloproteinases (MMPs) family function in irreversible matrix degradation and subsequent joint destruction in OA. 13 Previous reports showed that Interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) are two most potent catabolic factors that increase the production of inflammatory mediators and the expression of MMPs in chondrocytes. 14 Among these MMPs, MMP-13 has caught a lot of attention in that it was significantly overexpressed in both joints and articular cartilage in OA patients and could hardly be detected in normal tissues.…”