¹Berlin Institute of Health at Charité – Universitätsmedizin, BIH Center for Regenerative Therapies, Berlin, Deutschland
²Berlin Institute of Health and Center for Musculoskeletal Surgery, Julius Wolff Institute, Berlin, Deutschland
³Charité – Universitätsmedizin Berlin, Center for Musculoskeletal Surgery, Berlin, Deutschland
⁴imec, Leuven, Belgien

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Objectives and questions: Osteoarthritis (OA) affects over 590 million individuals worldwide [1] with no effective disease-modifying therapy available. Post-traumatic OA (PTOA), often caused by knee-joint injuries such as anterior cruciate ligament (ACL) ruptures, develops in about 50% of patients, even following reconstructive surgery to restore joint stability [2]. This suggests biological mechanisms beyond instability drive disease initiation, highlighting the urgent need to investigate early molecular and cellular events following trauma. Angiogenesis and capillarization are hallmarks and potential drivers of end-stage OA in synovial membrane (SM) and cartilage [3]. Interestingly, we have identified an early dysregulated vascular response to joint trauma failing to heal, leading to PTOA initiation [4]. Consequently, we hypothesize that neovascularization within the SM plays a role in PTOA initiation. Here, we aim to investigate the role of altered vascularization in the SM upon joint trauma, and to decipher the underlying mechanism.

Material and methods: We analyzed and compared SM samples from patients undergoing ACL reconstruction and autologous chondrocyte transfer, representing different stages of potential PTOA development, with end-stage OA samples. For characterization, the size, number, and distance of the vessels to the synovial lining layer were investigated. To study this dynamically, a human-based in vitro model is developed to simulate the vascular trauma response. This model allows the controlled study of angiogenesis, and the introduction of critical parameters influencing angiogenesis and capillarization, providing a platform for mechanistic modeling and testing of different therapeutic approaches.

Results: Obtained findings from clinical samples revealed altered CD31 expression in the SM, across early- or middle-stage PTOA, and end-stage OA. This indicated dynamic vascular changes are already present in the early phase of disease progression, and may play a role in PTOA initiation. Furthermore, this may be related to the early stage post intervention.

Discussion and conclusions: By uncovering early pathological events in PTOA initiation, we envision bridging the gap between clinical observations and mechanistic understanding of the SMs regulatory role during OA pathogenesis. This could potentially guide the development of targeted interventions to improve long-term joint health and patient outcomes following knee trauma.

References

[1] GBD Osteoarthritis Collaborators. Global, regional, and national burden of osteoarthritis, 1990–2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023;5(9):e508-e522. DOI: 10.1016/S2665-9913(23)00163-7
[2] Kraus VB, Hsueh MF. Molecular biomarker approaches to prevention of post-traumatic osteoarthritis. Nat Rev Rheumatol. 2024 May;20(5):272-89. DOI: 10.1038/s41584-024-01102-y
[3] Mapp PI, Walsh DA. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat Rev Rheumatol. 2012 May 29;8(7):390-8. DOI: 10.1038/nrrheum.2012.80
[4] Bolander J, Wilson A, Ory L, Moviglia G, Poehling G, Atala A. 658 - Trauma Intensity Steers the Onset of Functional or Dysfunctional Healing following Osteochondral Injuries in the Synovial Joint. Osteoarthr. Cartil. 2024;32(1):453–4. DOI: 10.1016/j.joca.2024.02.673