bioRxiv2018
RUNX2 is a transcription factor critical for chondrocyte maturation and normal endochondral bone formation. It promotes the expression of factors catabolic to the cartilage extracellular matrix and is shown to be upregulated in human osteoarthritic cartilage and in murine articular cartilage following joint injury. To date, in vivo studies of RUNX2 overexpression in cartilage have been limited to forced expression in osteochondroprogenitor cells preventing investigation into the effects of chondrocyte-specific RUNX2 overexpression during development or in postnatal articular cartilage. Here, we used the Rosa26Runx2 allele in combination with the inducible Col2a1CreERT2 transgene or the inducible AcanCreERT2 knock-in allele to achieve chondrocyte-specific RUNX2 overexpression (OE) during embryonic development or in the postnatal articular cartilage of adult mice, respectively. RUNX2 OE was induced at E13.5 for all developmental studies and resulted in a phenotype resembling chondrodysplasia at E18.5. Histology and in situ hybridization analyses suggest an early onset of chondrocyte hypertrophy and accelerated terminal maturation in the limbs of the RUNX2 OE embryos compared to control embryos. Additionally, RUNX2 OE resulted in enhanced TUNEL staining indicative of increased chondrocyte apoptosis throughout all regions of the growth plate. For all postnatal studies, RUNX2 OE was induced at 2 months of age. Surprisingly, no histopathological signs of OA or cartilage catabolism were observed even six months following induction of RUNX2 OE in postnatal animals. Using the meniscal/ligamentous injury (MLI), a surgical model of knee joint destabilization and meniscal injury, however, we found that chondrocyte-specific RUNX2 OE accelerates the progression of OA pathogenesis following joint trauma. Histomorphometry and OARSI scoring confirmed decreased cartilage area two months following injury in the RUNX2 OE joints compared to control joints. Further, the numbers of MMP13-positive and TUNEL-positive chondrocytes were significantly greater in the articular cartilage of the RUNX2 OE joints compared to control joints one month following injury. Collectively, our data support that RUNX2 OE in growth plate chondrocytes is sufficient to promote their hypertrophy and terminal maturation during development. While RUNX2 overexpression alone is surprisingly insufficient to induce catabolic changes to the postnatal articular cartilage, it can accelerate the progression of post-traumatic OA. These results suggest that although increased RUNX2 expression may predetermine the rate of OA onset and/or progression following traumatic joint injury, alone this change is not sufficient to initiate the OA degenerative process.