This proposal is from Dr. Linda Sandell, a cartilage biologist in the Departments of Orthopaedic Surgery and Cell Biology and Dr. James Cheverud, a population geneticist and morphologist in the Department of Anatomy and Neurobiology. Using strains related to the """"""""super healing"""""""" mouse (both recombinant inbred strains and an advanced intercross), we have defined phenotypes of articular cartilage regeneration and ear tissue regeneration and established a strong positive correlation between these two phenotypes. Furthermore, proof- of-concept studies demonstrate that the ability to heal articular cartilage may be associated with protection from post-traumatic osteoarthritis. This unique genetic resource will be used to test the association between ear wound healing, cartilage regeneration and osteoarthritis and to systematically identify genes that contribute to cartilage regeneration and thus to osteoarthritis development.
The specific aims of the current grant proposal are: (1) Test the correlation between articular cartilage regeneration and osteoarthritis in recombinant inbred lines of LG/J and SM/J, mapping to approximately 10 cM (2) Determine the distribution of articular cartilage regeneration and osteoarthritis in the advanced intercross f LG/J and SM/J, mapping these regions to sub-cM intervals containing 1-5 genes (3) Determine the cell and molecular mechanisms responsible for established strain differences in cartilage and stem cell responses in the strains that represent extremes of healing, and (4) Using a systems-educated candidate gene approach, validate genes through our """"""""Lend an Ear for Osteoarthritis"""""""" Campaign. The methods used to undertake these specific aims rely on the availability of recombinant inbred and advanced intercross strains of LG/J and SM/J with different abilities to regenerate cartilage and ear tissue combined with mouse surgical techniques for articular cartilage wounding and destabilization of the medial meniscus (DMM osteoarthritis model), analyzed by histology and micro-CT. Functional analyses of cartilage and stem cells will be performed in the strains that are extremes of healing. Proof of gene involvement will be established by using the DMM osteoarthritis model in knock-out mice. The outcome of this project will be the identification of genes affecting osteoarthritis development and articular cartilage regeneration in mice, providing high-quality candidates for probing the human genome.

Public Health Relevance

Osteoarthritis affects 35 million people in the USA alone with an expected doubling in the number of affected individuals over the next 20 years. Emerging evidence indicates that 40-75% of the variation in primary osteoarthritis is genetic, however littl information is available on the alleles that promote osteoarthritis or protect from osteoarthritis. Cartilage degeneration is the end result of osteoarthritis. It has been suspected that humans differ in their ability to repair cartilage over time and to withstand cartilage degeneration due t osteoarthritis. While correlating genes with human osteoarthritis has been difficult, we and others have recently demonstrated that certain strains of mice, MRL/MpJ, DBA/1 and specific recombinant inbred strains from the LG/J by SM/J intercross, are better able to repair cartilage and are protected from post-traumatic arthritis. In addition, we demonstrated a strong, positive correlation been articular cartilage regeneration and regeneration of outer ear tissues after wounding. Thus, we are now in a position to begin identifying the specific genes that contribute to cartilage regeneration and are involved in susceptibility and protection from osteoarthritis in mice. The results found in mice, a species that is amenable to genetic studies, will be immediately applicable to the human disease as most of the genes affect the same molecular signaling pathways in both species. Long term, an understanding of the genes that contribute to cartilage healing may allow us to enhance the intrinsic repair of cartilage before osteoarthritis develops to the point of cartilage degeneration. Knowledge of the players involved in sustaining a cartilage repair response will allow us to determine which individuals will be more susceptible to osteoarthritis. This could have a huge public health impact on the pain and disability from osteoarthritis if a propensity for the disease could be detected before it develops into a serious condition. These results would set the stage for the development of treatments and even cures for osteoarthritis years before the disease is currently detected. Early treatment would save billions of dollars in health care costs and work time lost.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Tyree, Bernadette
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Washington University
Schools of Medicine
Saint Louis
United States
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Brophy, R H; Zhang, B; Cai, L et al. (2018) Transcriptome comparison of meniscus from patients with and without osteoarthritis. Osteoarthritis Cartilage 26:422-432
Rai, Muhammad Farooq; Tycksen, Eric D; Sandell, Linda J et al. (2018) Advantages of RNA-seq compared to RNA microarrays for transcriptome profiling of anterior cruciate ligament tears. J Orthop Res 36:484-497
Chinzei, Nobuaki; Rai, Muhammad Farooq; Hashimoto, Shingo et al. (2018) Evidence for Genetic Contribution to Variation in Post-Traumatic Osteoarthritis in Mice. Arthritis Rheumatol :
Rai, Muhammad Farooq; Duan, Xin; Quirk, James D et al. (2017) Post-Traumatic Osteoarthritis in Mice Following Mechanical Injury to the Synovial Joint. Sci Rep 7:45223
Brophy, Robert H; Sandell, Linda J; Cheverud, James M et al. (2017) Gene expression in human meniscal tears has limited association with early degenerative changes in knee articular cartilage. Connect Tissue Res 58:295-304
Brophy, Robert H; Sandell, Linda J; Rai, Muhammad Farooq (2017) Traumatic and Degenerative Meniscus Tears Have Different Gene Expression Signatures. Am J Sports Med 45:114-120
Rai, Muhammad Farooq; Sandell, Linda J; Zhang, Bo et al. (2016) RNA Microarray Analysis of Macroscopically Normal Articular Cartilage from Knees Undergoing Partial Medial Meniscectomy: Potential Prediction of the Risk for Developing Osteoarthritis. PLoS One 11:e0155373
Christiansen, B A; Guilak, F; Lockwood, K A et al. (2015) Non-invasive mouse models of post-traumatic osteoarthritis. Osteoarthritis Cartilage 23:1627-38
Rai, Muhammad Farooq; Schmidt, Eric J; Hashimoto, Shingo et al. (2015) Genetic loci that regulate ectopic calcification in response to knee trauma in LG/J by SM/J advanced intercross mice. J Orthop Res 33:1412-23
Rai, Muhammad Farooq; Sandell, Linda J (2014) Regeneration of articular cartilage in healer and non-healer mice. Matrix Biol 39:50-5

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