Wang Xiaogang, Ji Luli, Wang Jing, Liu Changsheng
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China.
Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China.
Bioact Mater. 2023 Mar 30;27:138-153. doi: 10.1016/j.bioactmat.2023.03.014. eCollection 2023 Sep.
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 and . 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.
破骨细胞普遍参与骨稳态，其异常会导致诸如骨质疏松症等骨疾病。目前通过生化信号分子的临床策略往往由于对破骨细胞的管理失控而扰乱先天性骨代谢。因此，迫切需要一种精确调节破骨细胞分化的替代策略。为此，本研究提出了一个假设，即机械刺激可能是一种潜在策略。在此，创建了一种水凝胶来模拟生理骨微环境，其硬度范围为2.43千帕至68.2千帕。全面研究了基质硬度对破骨细胞行为的影响。结果表明，基质硬度可用于引导破骨细胞命运。特别是，增加的基质硬度抑制整合素β3反应性RhoA-ROCK2-YAP相关的机械转导并促进破骨细胞生成。值得注意的是，中等硬度水凝胶（M-凝胶）具有与血管相同的17.5千帕至44.6千帕的硬度，通过部分抑制机械转导促进前破骨细胞发育，随后促进骨缺损小鼠的血管再生和骨再生。我们的工作通过选择最佳基质硬度为精细调节破骨细胞分化提供了一种创新方法，并使我们能够进一步开发基于基质硬度的骨组织工程策略。
