Cartilage Biology and Joint Restorative Therapeutics Research

Osteoarthritis (OA) is among the most prevalent chronic human health disorders and the most common form of arthritis. It is among the leading cause of disability in Canada and worldwide, and with increasing life expectancy; OA is a major socioeconomic and clinical concern. In OA, cartilage is destroyed and synovium gets inflamed causing joint stiffness, pain and disability. The disease progresses relatively unnoticed; by the time that it is diagnosed, the damage is often so severe that treatments are no longer effective.

Specific mechanisms associated with the joint destruction during OA are largely unknown. Due to the lack of biomarkers, it is impossible to identify patients exhibiting early stages of OA, leading to severe joint destruction. Furthermore, due to poor understanding of the underlying disease mechanisms, no disease-modifying therapies to treat OA exist. Therefore, early detection and early intervention is critical to restore joint functions.
 


Major focus of Kapoor Lab:

Osteoarthritis Biomarkers (Early Detection):

Goal: Identification of reliable and specific OA Biomarkers that can assist in detecting and determining the degree of joint destruction during OA. Our biomarker exploration studies are currently focusing on two joints: knee and spine (facet). For biomarker exploration, we are employing a multi-tier approach using Next Generation Sequencing, metabolomics, cytokine-multiplexing etc in combination with patient demographics and risk factors. Our team of scientists within Kapoor lab and key collaborators including basic scientists, clinicians, epidemiologists, computational biologists are involved in this study.

Key Discovery:

1. Akihiro Nakamura, Y. Raja Rampersaud, A. Sharma, S.J. Lewis, B. Wu, P. Datta, K. Sundararajan, H. Endisha, E. Rossomacha, JS Rockel, I. Jurisica and Kapoor M. Identification of microRNA 181 and 4454 as novel mediators of facet cartilage degeneration. Journal of Clinical Investigation Insight. 2016;1(12) PMID: 27699225 Pubmed

Related News: Research team discovers two biomarkers that contribute to spine osteoarthritis: https://www.eurekalert.org/pub_releases/2016-08/uhn-rtd080316.php

 

Injectable Therapies to stop Joint Destruction During Osteoarthritis:

Goal: Identifying and targeting potential therapeutic targets that can reduce or stop joint inflammation, fibrosis, cartilage destruction and help restore joint function.
 

Kapoor Lab is currently working on three major injectable therapies:

 

1. Chondro-protective therapy: Chondrocyte cell death within the articular cartilage is the major event that initiates cartilage destruction during OA. Our recent studies suggest that autophagy proteins are crucial for the survival of chondrocytes within articular cartilage. We have identified crucial autophagy mediators that can help increase the survival of chondrocytes within articular cartilage. We are currently testing some major autophagy-activating agents in OA models to identify their chondro-protective potential.

Key Discoveries:

1.  Rockel J and Kapoor M. Autophagy: Controlling cell fate in Rheumatic Diseases: Nature Review Rheumatology. 2016 Sep;12(9):517-31 Pubmed

2.  Zhang Y, Vasheghani F, Li YH, Blati M, Simeone K, Fahmi H, Lussier B, Roughley P, Lagares D, Pelletier JP, Martel-Pelletier J, Kapoor M. Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from Osteoarthritis. Annals of the Rheumatic Diseases. 2015 Jul;74(7):1432-40. Pubmed

3. Vasheghani F, Zhang Y, Yinghua Li, Meryem Blati, et al and Kapoor M. PPARgamma deficiency results in severe accelerated Osteoarthritis associated with defective mTOR and autophagy signalling. Annals of The Rheumatic Diseases. 2015 Mar. 74(3):569-78. Pubmed

Related News: Genes play role in early onset of arthritis:  
https://www.thestar.com/life/health_wellness/2015/09/20/genes-play-role-in-early-onset-of-arthritis.html

 

2. microRNA Blockers: We have discovered some specific microRNAs that are elevated in the cartilage and biofluids of subjects with knee and spine OA. These microRNAs increase inflammation and catabolic activity in the cartilage and contribute to its degeneration. We are currently testing the efficacy and safety of microRNA inhibitors in preclinical spine and knee OA models.

Key Discovery:

1. Akihiro Nakamura, Y. Raja Rampersaud, A. Sharma, S.J. Lewis, B. Wu, P. Datta, K. Sundararajan, H. Endisha, E. Rossomacha, JS Rockel, I. Jurisica and Kapoor M. Identification of microRNA 181 and 4454 as novel mediators of facet cartilage degeneration. Journal of Clinical Investigation Insight. 2016;1(12) PMID: 27699225 Pubmed

Related News: Two Biomarkers that Contribute to Spine Osteoarthritis: https://www.sciencedaily.com/releases/2016/08/160804095150.htm

 

3. Anti-fibrotic therapy: We recently identified that soluble ephrin-B2 (shedded form of ephrin-B2 protein belonging to protein-tyrosine kinase family) as a novel pro-fibrotic mediator and as a potential anti-fibrotic therapeutic target. We specifically identified how ephrin-B2 is shed by ADAM10 metalloproteinase and how this shedded form of ephrin-B2 promotes tissue fibrosis. We are currently testing the therapeutic potential of targeting the ephrin pathway to limit fibrosis in animal models OA, scleroderma and idiopathic pulmonary fibrosis.

Key Discovery:

1. Lagares D, Ghassemi-Kakroodi P, Tremblay C, Santos A, Probst CK, Franklin A, Santos DM, Grasberger P, Ahluwalia N, Montesi SB, Shea BS, Black KE, Knipe R, Blati M, Baron M, Wu B, Fahmi H, Gandhi R, Pardo A, Selman M, Wu J, Pelletier JP, Martel-Pelletier J, Tager AM, Kapoor M. Nat Med. 2017 Oct 23. doi: 10.1038/nm.4419. Pubmed

Related News: Researchers Uncover a Pathway that Promotes Excessive Tissue Repair and Organ Malfunction. http://www.uhnresearch.ca/news/too-much-good-thing