An immunoregenerative approach to mitigate post-traumatic osteoarthritis after intra-articular fracture

AIMS: This study aimed to assess the effects of chondrogenic agents kartogenin (KGN) and KA9 in combination with anakinra (ANR), an interleukin (IL) 1 receptor antagonist (IL1RA) on post-traumatic osteoarthritis (PTOA) progression following intra-articular fractures (IAF). The hypothesis was that this immunoregenerative approach would promote osteochondral healing and alleviate PTOA more effectively than individual treatments or controls.

METHODS: Male Lewis rats (n = 78) underwent IAF, followed by weekly intra-articular injection of saline (control), KGN, or KA9 in conjunction with the systemic administration of saline (control) or ANR via osmotic pumps. Inflammatory and osteochondral markers were assessed through serum and synovial fluid analysis, micro-CT (µCT) for bone parameters, contrast-enhanced µCT for cartilage evaluation, histopathological analysis, and immunohistochemistry (IHC).

RESULTS: Immunoregenerative treatments did not adversely affect animal wellbeing. While local inflammation markers were minimally affected, some osteochondral remodelling markers indicated that KGN, KA9, and their combination with ANR reduced markers of osteochondral degradation. Bone analysis showed improved trabecular morphometry parameters and reduced bone surface with some treatments, and cartilage composition and thickness improved with treatments, although the effects were inconsistent across groups. Osteoarthritis Research Society International scores revealed location-specific variations in pathology, and IHC staining demonstrated intergroup differences in protein expression at different timepoints.

CONCLUSION: This study suggests that KGN and KA9 may offer some protection against PTOA by influencing cartilage and subchondral bone health, and that the combination with ANR shows potential for enhanced effects. However, the results were mixed, with no treatment group consistently demonstrating positive improvements across all outcomes. The complexity of developing a novel immunoregenerative therapy for PTOA is highlighted by the variability in treatment response.