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Chondrocyte-Specific RUNX2 Overexpression Accelerates Post-traumatic Osteoarthritis Progression in Adult Mice.
J Bone Miner Res. 2019 09; 34(9):1676-1689.JB

Abstract

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 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 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 articular cartilage of adult mice, respectively. RUNX2 OE was induced at embryonic day 13.5 (E13.5) for all developmental studies. 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. For all postnatal studies, RUNX2 OE was induced at 2 months of age. Surprisingly, no histopathological signs of cartilage degeneration were observed even 6 months following induction of RUNX2 OE. Using the meniscal/ligamentous injury (MLI), a surgical model of knee joint destabilization and meniscal injury, however, we found that RUNX2 OE accelerates the progression of cartilage degeneration following joint trauma. One month following MLI, 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 and 2 months following MLI, histomorphometry and Osteoarthritis Research Society International (OARSI) scoring revealed decreased cartilage area in the RUNX2 OE joints. Collectively, these results suggest that although RUNX2 overexpression alone may not be sufficient to initiate the OA degenerative process, it may predetermine the rate of OA onset and/or progression following traumatic joint injury. © 2019 American Society for Bone and Mineral Research.

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Authors+Show Affiliations

Catheline SE
Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
Hoak D
Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA. Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA.
Chang M
Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA. Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA.
Ketz JP
Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA. Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA.
Hilton MJ
Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.
Zuscik MJ
Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA. Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA. Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Orthopedic Research Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Jonason JH
Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA. Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA.

MeSH

AgingAnimalsAnimals, NewbornCartilage, ArticularChondrocytesCore Binding Factor Alpha 1 SubunitDisease ProgressionFemaleHumansKnee JointMaleMatrix Metalloproteinase 13MiceOrgan SpecificityOsteoarthritisOsteochondrodysplasiasPhenotypeWounds and Injuries

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

31189030

Citation

Catheline, Sarah E., et al. "Chondrocyte-Specific RUNX2 Overexpression Accelerates Post-traumatic Osteoarthritis Progression in Adult Mice." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 34, no. 9, 2019, pp. 1676-1689.
Catheline SE, Hoak D, Chang M, et al. Chondrocyte-Specific RUNX2 Overexpression Accelerates Post-traumatic Osteoarthritis Progression in Adult Mice. J Bone Miner Res. 2019;34(9):1676-1689.
Catheline, S. E., Hoak, D., Chang, M., Ketz, J. P., Hilton, M. J., Zuscik, M. J., & Jonason, J. H. (2019). Chondrocyte-Specific RUNX2 Overexpression Accelerates Post-traumatic Osteoarthritis Progression in Adult Mice. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 34(9), 1676-1689. https://doi.org/10.1002/jbmr.3737
Catheline SE, et al. Chondrocyte-Specific RUNX2 Overexpression Accelerates Post-traumatic Osteoarthritis Progression in Adult Mice. J Bone Miner Res. 2019;34(9):1676-1689. PubMed PMID: 31189030.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chondrocyte-Specific RUNX2 Overexpression Accelerates Post-traumatic Osteoarthritis Progression in Adult Mice. AU - Catheline,Sarah E, AU - Hoak,Donna, AU - Chang,Martin, AU - Ketz,John P, AU - Hilton,Matthew J, AU - Zuscik,Michael J, AU - Jonason,Jennifer H, Y1 - 2019/06/12/ PY - 2018/11/26/received PY - 2019/03/18/revised PY - 2019/04/03/accepted PY - 2019/6/13/pubmed PY - 2020/9/23/medline PY - 2019/6/13/entrez KW - ANIMAL MODELS KW - CELL/TISSUE SIGNALING KW - CHONDROCYTE AND CARTILAGE BIOLOGY KW - DISEASES AND DISORDERS OF/RELATED TO BONE KW - GENETIC ANIMAL MODELS KW - HYPERTROPHY KW - OSTEOARTHRITIS KW - POST-TRAUMATIC OSTEOARTHRITIS KW - RUNX2 KW - TRANSCRIPTION FACTORS SP - 1676 EP - 1689 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J Bone Miner Res VL - 34 IS - 9 N2 - 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 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 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 articular cartilage of adult mice, respectively. RUNX2 OE was induced at embryonic day 13.5 (E13.5) for all developmental studies. 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. For all postnatal studies, RUNX2 OE was induced at 2 months of age. Surprisingly, no histopathological signs of cartilage degeneration were observed even 6 months following induction of RUNX2 OE. Using the meniscal/ligamentous injury (MLI), a surgical model of knee joint destabilization and meniscal injury, however, we found that RUNX2 OE accelerates the progression of cartilage degeneration following joint trauma. One month following MLI, 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 and 2 months following MLI, histomorphometry and Osteoarthritis Research Society International (OARSI) scoring revealed decreased cartilage area in the RUNX2 OE joints. Collectively, these results suggest that although RUNX2 overexpression alone may not be sufficient to initiate the OA degenerative process, it may predetermine the rate of OA onset and/or progression following traumatic joint injury. © 2019 American Society for Bone and Mineral Research. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/31189030/Chondrocyte_Specific_RUNX2_Overexpression_Accelerates_Post_traumatic_Osteoarthritis_Progression_in_Adult_Mice_ DB - PRIME DP - Unbound Medicine ER -