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Background: Bone homeostasis is a dynamic process maintained by osteoblasts and osteoclasts, which may be regulated by excessive mechanical stress (EMS).Objectives: Our study aimed to explore the relationship between osteogenic differentiation of BMSCs and EMS-activated osteoclast differentiation of RAW 264.7 cells in order to optimise orthodontic treatment. Methods:We established the model of EMS in vivo and in vitro. In vivo, HE, Safranin-O staining, micro-CT, and immunofluorescence double-labelling were utilised to assess the changes in condylar, the distributions of osteoblasts, osteoclasts and MAPKs. In vitro, the effects of EMS-activated osteoclast differentiation exerting on osteogenic differentiation of BMSCs were observed by Western Blot, qRT-PCR and Alizarin Red staining. Furthermore, the role of MAPKs in this progress was explored by using inhibitors of MAPKs and co-culture supernatants. Results:In vivo, EMS led to the degradation of condylar cartilage and destruction of subchondral bone, diagnosed as temporomandibular joint osteoarthritis (TMJ OA).Osteoclasts and osteoblasts were both enriched in subchondral bone, but osteoclast predominated. The expressions of p-JNK, p-ERK1/2, and p-p38 were all activated in vitro and in vivo, which were localised mainly in the Trap+ area in subchondral bone.Interestingly, only the inactivation of p-ERK1/2 in osteoclasts significantly inhibited the osteogenic differentiation of BMSCs in vitro. This revealed that p-ERK1/2 played a key role in the osteoclasts-induced osteogenic differentiation of BMSCs. Conclusion:Our results proved that EMS led to TMJ OA, in which upregulated p-ERK1/2 in osteoclasts was mechanosensitive and facilitated the osteogenic differentiation of BMSCs.