TAT-Beclin-1 induces severe synovial hyperplasia and does not protect from injury-induced osteoarthritis in mice.

Summary Object Autophagy maintains cartilage homeostasis and is compromised during osteoarthritis (OA), contributing to cartilage degeneration. We sought to determine if D-isomer TAT-Beclin-1, a potent inducer of autophagy, could attenuate post-traumatic OA in mice. Methods Ten-week-old mice underwent destabilization of the medial meniscus (DMM) surgery to induce post-traumatic OA, or sham surgery (control), and injected intra-articularly with D-isomer TAT-Beclin-1 (0.5-2 mg/kg) or PBS one-week post-surgery for up to 9 weeks. Mice were sacrificed at two or 10 weeks post-surgery. Knee joint sections were evaluated by histopathology for cartilage degeneration and synovitis, and immunostaining for key markers of autophagy (LC3B), cell proliferation (nuclear Ki67), activated fibroblasts (αSMA), and hematopoietic-origin cells (CD45). Results All D-isomer TAT-Beclin-1-treated DMM mice had no difference in the degree of cartilage degeneration compared to PBS-injected DMM mice. Surprisingly, all D-isomer TAT-Beclin-1-treated mice exhibited substantial synovial hyperplasia, with increased cellularity and ECM deposition (fibrosis-like phenotype), as compared to PBS-injected mice. Synovial effects of D-isomer TAT-Beclin-1 were dose and injection frequency dependent. An increased percentage of cells positive for LC3B and nuclear Ki67 were found in the synovial intima early after injection, which persisted after frequent injections. Conclusions D-isomer TAT-Beclin-1 did not attenuate cartilage degeneration but rather induced synovial hyperplasia associated with increased expression of key markers of autophagy and cell proliferation, and a fibrosis-like phenotype, independent of markers of fibroblast activation or persistent hematopoietic-origin cell infiltration. These data suggest that if not tissue-targeted, caution should be taken using autophagy activators due to diverse cellular responses in the joint.