Work

Postnatal deletion of Phlpp1 in chondrocytes delays post-traumatic osteoarthritis in male mice

Year: 2024

Type: article

Abstract: Objective Osteoarthritis is a chronic, debilitating disease that causes long-term pain and immobility. Germline deletion of Phlpp1 or administration of small molecules that inhibit Phlpp1 prevents post-traumatic osteoarthritis (PTOA) in mice. However, the chondrocyte-intrinsic role of Phlpp1 in PTOA progression is unknown. The objective of this study was to determine how postnatal, chondrocyte-directed deletion of Phlpp1 affects PTOA progression in the presence or absence of Phlpp inhibitors. Design Phlpp1 fl/fl ; Agc-Cre ERT2 and Agc-Cre ERT2 mice were injected with tamoxifen at 12 weeks of age to generate Phlpp1-CKO AgcERT and control (AgcERT) groups. Male mice underwent surgery to destabilize the medial meniscus (DMM) at 17 weeks of age. A separate cohort of male Phlpp1-CKO AgcERT mice were administered an intra-articular injection of NSC117079, a Phlpp1/2 inhibitor, or saline seven weeks after DMM surgery. Activity and mechanical allodynia were monitored throughout the experiment and cartilage damage was evaluated 12 weeks post-surgery. Results Phlpp1-CKO AgcERT mice had less cartilage damage than AgcERT littermates 12 weeks after DMM surgery but exhibited no differences in activity. Prg4 expression was also higher in articular chondrocytes of Phlpp1-CKO AgcERT mice. Intra-articular administration of NSC117079 to Phlpp1-CKO AgcERT mice improved cartilage structure, subchondral bone sclerosis, and mechanical allodynia at 12 weeks post-DMM. Conclusions Postnatal deletion of Phlpp1 in chondrocytes attenuates DMM-induced cartilage damage and subchondral bone sclerosis but does not prevent pain-related behaviors. Intra-articular injection of Phlpp inhibitors delays mechanical allodynia in Phlpp1-CKO AgcERT mice. These data indicate that Phlpp1 in chondrocytes affects articular cartilage structure after injury, but pain-related behaviors are controlled by Phlpp1 or Phlpp2 in other cell types.

Source: Osteoarthritis and Cartilage Open

DOI: 10.1016/j.ocarto.2024.100525