Abstract
The E-74 like factor 3 (ELF3) is a transcription factor induced by inflammatory factors in various cell types, including chondrocytes. ELF3 levels are elevated in human cartilage from patients with osteoarthritis (OA), and ELF3 contributes to the IL-1β-induced expression of genes encoding Mmp13, Nos2, and Ptgs2/Cox2 in chondrocytes in vitro. Here, we investigated the contribution of ELF3 to cartilage degradation in vivo, using a mouse model of OA. To this end, we generated mouse strains with cartilage-specific Elf3 knockout (Col2Cre:Elf3f/f) and Comp-driven Tet-off-inducible Elf3 overexpression (TRE-Elf3:Comp-tTA). To evaluate the contribution of ELF3 to OA, we induced OA in 12-week-old Col2Cre:Elf3f/f and 6-month-old TRE-Elf3:Comp-tTA male mice using the destabilization of the medial meniscus (DMM) model. The chondrocyte-specific deletion of Elf3 led to decreased levels of IL-1β- and DMM-induced Mmp13 and Nos2 mRNA in vitro and in vivo, respectively. Histological grading showed attenuation of cartilage loss in Elf3 knockout mice compared to wild type (WT) littermates at 8 and 12 weeks following DMM surgery that correlated with reduced collagenase activity. Accordingly, Elf3 overexpression led to increased cartilage degradation post-surgery compared to WT counterparts. Our results provide evidence that ELF3 is a central contributing factor for cartilage degradation in post-traumatic OA in vivo.
Highlights
E-74 like factor 3 (ELF3) is expressed in the cartilage and synovium of patients with rheumatoid arthritis and OA12,17,18
We showed previously that ELF3 mRNA and protein levels are increased in human OA cartilage, and our in vitro data in human and mouse primary chondrocytes provided evidence for the pivotal
We show that ELF3 contributes to increased collagenase activity and cartilage degradation in vivo, in a mouse model of post-traumatic OA, and that ELF3 overexpression accelerates cartilage degradation concomitant to post-traumatic OA disease
Summary
ELF3 is expressed in the cartilage and synovium of patients with rheumatoid arthritis and OA12,17,18. We showed that ELF3 represses the expression of the type II collagen gene (COL2A1) by directly binding to the COL2A1 promoter[18] and disrupting the activator functions of Sox[9] and CBP/p30019. We showed that ELF3 binds to and transactivates the MMP13 promoter in chondrocytes, thereby mediating IL-1β- and TNFα-driven MMP13 gene expression[17]. These results suggest that ELF3 plays a critical role in cartilage remodeling in OA disease. Using mice with Col2a1-driven Elf[3] knockout (Elf3-cKO) or Comp-driven Tet-Off inducible overexpression of Elf[3] (Elf3-Tg) subjected to destabilization of the medial meniscus (DMM), we show that Elf[3] accounts, in large part, for the expression and activity of Mmp[13] in articular chondrocytes in vivo
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