Osteoarthritis (OA) is a multifactorial disease, and recent data suggested that cell cycle-related proteins play a role in OA pathology. Cyclin-dependent kinase (CDK) inhibitor 1 (p21) regulates activation of other CDKs, and recently, we reported that p21 deficiency induced susceptibility to OA induced by destabilization of the medial meniscus (DMM) surgery through STAT3-signaling activation. However, the mechanisms associated with why p21 deficiency led to susceptibility to OA by the STAT3 pathway remain unknown. Therefore, we focused on joint inflammation to determine the mechanisms associated with p21 function during in vitro and in vivo OA progression. p21-knockout (p21(-/-)) mice were used to develop an in vivo OA model, and C57BL/6 (p21(+/+)) mice with the same background as the p21(-/-) mice were used as controls. Morphogenic changes were measured using micro-CT, IL-1 serum levels were detected by ELISA, and histological or immunohistological analyses were performed. Our results indicated that p21-deficient DMM-model mice exhibited significant subchondral bone destruction and cartilage degradation compared with wild-type mice. Immunohistochemistry results revealed p21(-/-) mice susceptibility to OA changes accompanied by macrophage infiltration and enhanced MMP-3 and MMP-13 expression through IL-1-induced NF-B signaling. p21(-/-) mice also showed subchondral bone destruction according to micro-CT analysis, and cathepsin K staining revealed increased numbers of osteoclasts. Furthermore, p21(-/-) mice displayed increased serum IL-1 levels, and isolated chondrocytes from p21(-/-) mice indicated elevated MMP-3 and MMP-13 expression with phosphorylation of IB kinase complex in response to IL-1 stimulation, whereas treatment with a specific p-IB kinase inhibitor attenuated MMP-3 and MMP-13 expression. Our results indicated that p21-deficient DMM mice were susceptible to alterations in OA phenotype, including enhanced osteoclast expression, macrophage infiltration, and MMP expression through IL-1-induced NF-B signaling, suggesting that p21 regulation may constitute a possible therapeutic strategy for OA treatment. (c) 2017 American Society for Bone and Mineral Research.