骨细胞Wnt促进骨折愈合机制及其转化应用初步研究

骨折愈合相当于完成胚胎时期骨发育过程。临床上仍有10%的骨折产生延迟愈合或者不愈合，目前尚无理想药物对症干预。我们发现：1)骨细胞是四种成骨因素的靶细胞；2)组成性激活骨细胞Wnt信号提高骨形成和骨吸收，缩短一半小鼠骨折愈合时间，是目前最快的愈合速度，而且产生很小的血痂和骨痂，在抑制骨吸收导致骨折不愈合条件下，也照样愈合，不同于常规愈合。因而提出假说：骨细胞Wnt信号加速骨折愈合。本研究用新构建的模型，实时激活和失活骨细胞Wnt信号，比较正常骨发育，应用自主研发的生物材料与细胞一体化3D打印设备制备骨类器官功能模块，旨在揭示骨细胞Wnt信号快速修复正常的和不愈合的骨折的分子机制。用筛选出的小分子化合物，特异激活骨细胞Wnt，逐步上大动物模型验证其功能。为临床转化提供实验数据，促进骨发育生物学理论和技术进入临床研发阶段。

Fracture healing and bone repair are the courses of skeletal development, similar to that in embryogenesis. However, there is 10% of cases in the form of delayed and nonunion fracture (DFNs) due to diabetes, osteoporosis, smoking, alcoholic, and steroids etc. and there is no approved pharmacological agents aiming at the DNFs. .We found that: 1) osteocytes are the targeting cells responsible for bone anabolism by mechanical stimulation, PTH intermittent treatment, and constitutively active PTH receptor in osteocytes ; 2) constitutive activation of Wnt signaling in osteocytes improves bone formation and bone absorption, shortens a half of time for fracture healing in mice, which is the fastest healing speed at present with the very small hematoma and bone callus. Even under the condition of inhibiting bone absorption leading to nonunion of fracture, it also heals as usual, which is different from conventional fracture healing. .Therefore, we hypothesis that Wnt signaling in osteocytes accelerates fracture healing with specific mechanisms. In this study, we use newly constructed models to activate and inactivate Wnt signal in osteocytes to test the hypothesis, as compared to the bone development under normal condition. Using the self-developed biomaterial and cell integrated 3D printing device to prepare the functional modules of bone organs, aming to reveal the molecular mechanisms by which Wnt signaling in osteocytes accelerates normal and heals nonunion fracture. Using the selected small molecule compounds to activate Wnt signal in osteocytes specifically, verifying its function with larger animal models. The above research will provide experimental data for clinical transformation and promotes the biological theory and technology of bone development into the clinical research and development stage.