This proposal has the potential to transform the area of anterior cruciate ligament (ACL) degeneration associated with ageing and will provide novel information on the prevention of knee joint osteoarthritis (OA).
This project will identify small molecules in cell-derived particles from ageing and diseased ACL that may play an important role in the development of knee joint OA. Furthermore identification of tissue-specific cell derived particles within ageing ACLs could be used as future therapies to prevent the progression of OA.
The ACL is the most frequently damaged ligament of the human knee joint following traumatic injuries in sports such as rugby and football and following age-related ligament breakdown, leading to joint instability, reduced mobility and the eventual development of knee joint OA. Age-related ligament breakdown and disease leads to ACL tears following non-contact injuries which are not related to a direct external trauma as would occur in contact sports.
The incidence of age-related ACL breakdown is increasing in our ageing population and currently the mechanisms of this disease leading to knee joint OA are poorly understood. Additionally there is no early diagnosis or treatment for this condition. Early intervention in ACL disease may be able to decelerate OA development/progression, postponing total knee joint replacement with significant benefits for patients and OA-related health care costs.
The mechanisms involved in age-related ACL degeneration are poorly understood, but we have identified changes in small molecules (small non-coding RNAs) in diseased ACLs which are associated with ligament injury. These small molecules can be transferred between tissues in the knee joint in small cell-derived particles (extracellular vesicles) and may have an important regulatory role in the development of OA.
We have identified extracellular vesicles in several knee joint tissues including the ACL, joint fluid and cartilage lining the joint surface, and have demonstrated the transfer of small molecules within these vesicles between knee joint cartilage and the tissue lining the knee joint; the synovium. However, identification of these small molecules within the ACL involved in this transfer and their cargo within the joint vesicles is still unknown.
This project will identify the small molecules within these vesicles from aged and diseased ACLs as early diagnostic markers for this condition and investigate the biological role of these small molecules on other knee joint tissues as potential treatment targets for OA.
1.Define the biological response of knee joint tissues to treatment with ACL EVs from aged and diseased ACLs from osteoarthritic knee joints.
Outcome: Identification of the biological impact of EVs from aged and diseased OA ACLs on the cellular phenotype of healthy knee joint cell lines, determining the role of EVs in disease biology
2. Identify the EV sncRNA cargo released from ACLs from aged and diseased osteoarthritic knee joints. Outcome: Age and osteoarthritis-related sncRNAs will be identified in EVs derived from ACL ligamentocytes, demonstrating the underpinning biological mechanisms of the ACL EVs and their role within the knee joint organ
3. Confirm the presence of the EV sncRNA cargo released from ACLs in the SF from aged and diseased osteoarthritic knee joints. Outcome: Generation of data supporting the first part of our hypothesis that ACL sncRNA EV cargo are present in the knee joint SF, demonstrating their utility as mediators of disease modification within the ageing and osteoarthritic-affected knee joint.
4. Determine which discriminating age and disease-related EV derived sncRNAs are sufficient to provoke disease-relevant effects on the key cell types within the knee joint organ. Outcome: The bioinformatic modelling will identify potential signalling and biological pathways altered by the EV sncRNAs, whilst the experimental assays will provide the proof that these sncRNAs are transferred to recipient cells of the knee joint and the extent of the biological effect they confer.
Ensuring our research serves a translational benefit
This study is partnered with the IACD Patient Involvement Panel. Presentations are made to a cohort of patients who live with age related conditions, particularly OA, on the development and progress of the study.
These meeting allow our researchers the opportunity to ensure that their work remains guided toward creating clinical benefit to those living with osteoarthritis.