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

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.