Deletion of Runx2 in Articular Chondrocytes Decelerates the Progression of DMM-Induced Osteoarthritis in Adult Mice

Abstract

Runx2 may play an important role in development of osteoarthritis (OA). However, the specific role of Runx2 in articular chondrocyte function and in OA development in adult mice has not been fully defined. In this study, we performed the destabilization of the medial meniscus (DMM) surgery at 12-week-old mice to induce OA in adult Runx2 Agc1CreER mice, in which Runx2 was specifically deleted in Aggrecan-expressing chondrocytes by administering tamoxifen at 8-weeks of age. Knee joint samples were collected 8- and 12-weeks post-surgery and analyzed through histology, histomorphometry and micro-computed tomography (μCT). Our results showed that severe OA-like defects were observed after DMM surgery in Cre-negative control mice, including articular cartilage degradation and subchondral sclerosis, while the defects were significantly ameliorated in Runx2 Agc1CreER KO mice. Immunohistochemical (IHC) results showed significantly reduced expression of MMP13 in Runx2 Agc1CreER KO mice compared to that in Cre-negative control mice. Results of quantitative reverse-transcription PCR (qRT-PCR) demonstrated that expression of the genes encoding for matrix degradation enzymes was significantly decreased in Runx2 Agc1CreER KO mice. Thus, our findings suggest that inhibition of Runx2 in chondrocytes could at least partially rescue DMM-induced OA-like defects in adult mice.

Chondrocyte-Specific RUNX2 Overexpression Accelerates Post-traumatic Osteoarthritis Progression in Adult Mice

“…It has been shown that global haploinsufficiency or chondrocyte‐specific loss of Runx2 can inhibit the progression of PTOA following traumatic joint injury . Because we did not find that RUNX2 OE alone in articular chondrocytes was sufficient to promote cartilage degeneration, however, we next tested whether chondrocyte‐specific RUNX2 OE could affect the progression of OA in the injured joint environment.…”

Dwarfism in homozygous Agc1CreERT mice is associated with decreased expression of aggrecan

“…One article reported the use of Agc Cre/Cre mice for their analysis (Maihiot et al, 2015). However, most of the articles do not state if Agc +/Cre or Agc Cre/Cre mice were used for phenotypic analysis (Shen et al, 2017; Liao et al, 2017; Hu et al, 2017; Sinha et al, 2017; Jing et al, 2015, 2016; Liu et al, 2015; Zhou et al 2014; Ono et al, 2014; Jing et al 2014; Henry et al, 2012). Therefore, caution must be exercised when interpreting data using this model as Agc Cre/Cre mice themselves have a skeletal phenotype.…”

“…Tamoxifen treatment results in nuclear translocation of the Cre-ERT fusion protein and subsequent excision of a floxed gene. Several studies have utilized the Agc Cre model to investigate the role of target genes in developing cartilage tissue (Shen et al, 2017; Liao et al, 2017; He et al, 2017; Hu et al, 2017; Sinha et al, 2017; Jing et al 2016; Liu et al, 2015; Maihiot et al, 2015; Zhou et al 2014; Ono et al, 2014; Jing et al 2014; 2013; Henry et al, 2012). Prior to breeding with our floxed mice, we noted variable weight and size among the Agc Cre littermates.…”

Deletion of Runx2 in condylar chondrocytes disrupts TMJ tissue homeostasis

“…In addition, Runx2 was also reported to influence the pathogenesis of OA through chondrocyte hypertrophy and matrix breakdown after the induction of joint instability (Kamekura et al, 2006). Our previous study showed that deletion of Runx2 in Aggrecan-expressing articular chondrocytes could decelerate the OA progression in adult mice (Liao et al, 2017). These findings suggest the importance of Runx2 in regulation of chondrocyte hypertrophy.…”