Matrix stiffness regulates osteoclast fate through integrin-dependent mechanotransduction

Osteoclasts ubiquitously participate in bone homeostasis, and their aberration leads to bone diseases, such as osteoporosis. Current clinical strategies by biochemical signaling molecules often perturb innate bone metabolism owing to the uncontrolled management of osteoclasts. Thus, an alternative strategy of precise regulation for osteoclast differentiation is urgently needed. To this end, this study proposed an assumption that mechanic stimulation might be a potential strategy. Here, a hydrogel was created to imitate the physiological bone microenvironment, with stiffnesses ranging from 2.43kPa to 68.2kPa. The impact of matrix stiffness on osteoclast behaviors was thoroughly investigated. Results showed that matrix stiffness could be harnessed for directing osteoclast fate in vitro and in vivo. In particular, increased matrix stiffness inhibited the integrin β3-responsive RhoA-ROCK2-YAP-related mechanotransduction and promoted osteoclastogenesis. Notably, preosteoclast development is facilitated by medium-stiffness hydrogel (M-gel) possessing the same stiffness as vessel ranging from 17.5 kPa to 44.6 kPa by partial suppression of mechanotransduction, which subsequently encouraged revascularization and bone regeneration in mice with bone defects. Our works provide an innovative approach for finely regulating osteoclast differentiation by selecting the optimum matrix stiffness and enable us further to develop a matrix stiffness-based strategy for bone tissue engineering.