Zhiqing Cai, Zhimin Zhang, Yuxin Wang, Shencai Liu, Jiarong Leng, Yun Chu, Jihang Liu, Yingying Fang, Bochong Chen, Wenquan Liang, Hong Wang, Lu Zhang, Weiguo Zou, Fan Yang, Qiancheng Song, Di Lu, Xiaochun Bai
Traumatic brain injury (TBI) accelerates bone healing and induces heterotopic ossification, raising the question of whether an injured brain benefits from bone. Here we reveal that dynamic compressive tibial axial loading (DCTAL), a model of tibial bone compression, increased survival and promoted motor and cognitive recovery after stroke and TBI in mice, as well as in pig TBI models. DCTAL reduced neuron loss, attenuated chronic inflammation and astrogliosis and stimulated neuronal regeneration after TBI. Deletion of the mechanosensory channel Piezo1 in osteocytes reversed these benefits, while serum from DCTAL mice recapitulated them. Osteocytes transduced mechanical signals to directly secrete factors such as IL-1R2, APOL11a and HSP70, while indirectly increasing serum levels of BDNF, PF4 and dopamine. These factors synergistically protected against TBI. Altogether, we establish a bone-brain axis in which bone endocrine function can be modulated by mechanical forces to enhance brain repair after injury.