--- - |2- We have generated Axin1 conditional knockout (KO) mice by targeting aggrecan‐expressing condylar cartilage cells in the temporomandibular joint (TMJ). The Axin1 conditional KO mice showed TMJ osteoarthritis (OA)‐like phenotype, probably through activation of β‐catenin and fibroblast growth factor (FGF) signaling. Osteoarthritis (OA) in the temporomandibular joint (TMJ) is a degenerative disease in the adult, which is characterized by the pathological degeneration of condylar cartilage. Axin1 plays a critical role in the regulation of cartilage development and homeostasis. To determine the role of Axin1 in TMJ tissue at the adult stage, we generated Axin1Agc1ER mice, in which Axin1 was deleted in aggrecan‐expressing chondrocytes at 2 months of age. Histology, histomorphometry, and immunostaining analyses were performed using TMJ tissues harvested from 4‐ and 6‐month‐old mice after tamoxifen administration. Total RNA isolated from TMJ cartilage of 6‐month‐old mice was used for gene expression analysis. Progressive OA‐like degeneration was observed in condylar cartilage in Axin1 knockout (KO) mice with loss of surface continuity and the formation of vertical fissures. In addition, reduced alcian blue staining in condylar cartilage was also found in Axin1 KO mice. Immunostaining and reverse transcription quantitative polymerase chain reaction (qRT‐PCR) assays revealed disturbed homeostasis in condylar cartilage with increased expressions of MMP13 and Adamts5 and decreased lubricin expression in Axin1‐deficient chondrocytes. Less proliferative cells with increased hypertrophic and apoptotic activities were presented in the condylar cartilage of Axin1Agc1ER KO mice. As a scaffolding protein, the deletion of Axin1 stimulated not only the β‐catenin but also the fibroblast growth factor (FGF) signaling via extracellular signal‐regulated protein kinases 1 and 2 (ERK1/2) activation. The qRT‐PCR results showed an increased expression of Fgfr1 in Axin1 KO cartilage. Overall, the deletion of Axin1 in condylar chondrocytes altered the β‐catenin and FGF/ERK1/2 signaling pathways, thus cooperatively contribute to the cartilage degeneration. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1720-1729, February 2019. '