gms | German Medical Science

Objectives: Approximately 40% of patients suffering from joint trauma such as anterior crucial ligament rupture develop post traumatic osteoarthritis (PTOA), and the number remains at 37% following reconstruction surgery. This suggest that PTOA is not solely developed as a function of impaired mechanical stability, but largely due to the initial biological trauma. Consequently, we hypothesized that PTOA initiation is caused by an injury-related signal leading to an imbalance in the activation of the signaling cascades during the transition from the pro-inflammatory to the pro-regenerative healing phase. Identifying the initial cause and subsequent signaling events that leads to PTOA initiation would enable improved diagnostic tools, guide therapeutic targets and potentially prevention.

Methods: Small (SD) and large (LD) full-thickness osteochondral defects (OCD) were created in the trochlear groove of rats. Healing was characterized after 96-hours, one, four, and twelve weeks post defect creation. Pathological evaluation upon OCD creation confirmed four distinct degrees of healing after 12 weeks, depending on defect size and immune status.

Results and conclusion: Analysis of healing one week post OCD creation confirmed a corresponding trend between the healing potential to extracellular matrix (ECM) production, progenitor- and immune cell activation. The results confirmed that both the availability of mature T-cells and defect size significantly affects the healing potential (p<0.5). scRNASeq confirmed unique inflammatory and progenitor cell populations present within the defect area in the functional SD healing model. Next, analysis of cellular communication between specific populations was performed. Specifically, elevated growth arrest specific (GAS)-related signaling was found between inflammatory macrophages in the dysfunctional healing models, compared to the healing model. This could be further correlated to elevated production of reactive oxygen species (ROS) 96h post injury. To test whether the elevated ROS in the non-healing models was the underlying cause for the failed tissue regeneration, an immunomodulatory cell treatment was developed based on joint-activated and pro-regenerative immune cells that was co-cultured with placenta derived progenitor cells. Upon intra-articular injection one week post OCD creation, restored healing potential was confirmed after 11 weeks. Specifically, the immunomodulatory cell treatment reduced the elevated ROS-related damage and improved the OCD healing potential in the three models of dysfunctional healing, with a fully regenerated articular unit confirmed based on histology, OARSI scoring and IHC analysis for Collagen type 2 and Lubricin.

These results confirm the integral role of the balanced activation of immune- and skeletal progenitor cells for functional osteochondral regeneration and restored joint homeostasis. In addition, the immunomodulatory therapy provides an early intervention therapy to avoid the initiation of post-traumatic OA.