Song Deye, He Guangxu, Song Fangfang, Wang Zhepeng, Liu Xiaochen, Liao Lele, Ni Jiangdong, Silva Matthew J, Long Fanxin
1Department of Orthopedics, The Second Xiangya Hospital, Central South University, Hunan, 410011 PR China.
2Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110 USA.
Bone Res. 2020 Feb 3;8:4. doi: 10.1038/s41413-019-0081-8. eCollection 2020.
There remain unmet clinical needs for safe and effective bone anabolic therapies to treat aging-related osteoporosis and to improve fracture healing in cases of nonunion or delayed union. Wnt signaling has emerged as a promising target pathway for developing novel bone anabolic drugs. Although neutralizing antibodies against the Wnt antagonist sclerostin have been tested, Wnt ligands themselves have not been fully explored as a potential therapy. Previous work has demonstrated Wnt7b as an endogenous ligand upregulated during osteoblast differentiation, and that Wnt7b overexpression potently stimulates bone accrual in the mouse. The earlier studies however did not address whether Wnt7b could promote bone formation when specifically applied to aged or fractured bones. Here we have developed a doxycycline-inducible strategy where Wnt7b is temporally induced in the bones of aged mice or during fracture healing. We report that forced expression of Wnt7b for 1 month starting at 15 months of age greatly stimulated trabecular and endosteal bone formation, resulting in a marked increase in bone mass. We further tested the effect of Wnt7b on bone healing in a murine closed femur fracture model. Induced expression of Wnt7b at the onset of fracture did not affect the initial cartilage formation but promoted mineralization of the subsequent bone callus. Thus, targeted delivery of Wnt7b to aged bones or fracture sites may be explored as a potential therapy.
对于治疗与衰老相关的骨质疏松症以及改善骨不连或延迟愈合情况下的骨折愈合，安全有效的骨合成代谢疗法仍存在未满足的临床需求。Wnt信号通路已成为开发新型骨合成代谢药物的一个有前景的靶标途径。尽管针对Wnt拮抗剂硬化蛋白的中和抗体已进行了测试，但Wnt配体本身作为一种潜在疗法尚未得到充分探索。先前的研究已证明Wnt7b是成骨细胞分化过程中上调的一种内源性配体，并且Wnt7b过表达能有效刺激小鼠的骨量增加。然而，早期研究并未探讨Wnt7b特异性应用于老龄或骨折骨骼时是否能促进骨形成。在此，我们开发了一种强力霉素诱导策略，可在老龄小鼠的骨骼中或骨折愈合期间适时诱导Wnt7b表达。我们报告称，从15月龄开始强制表达Wnt7b持续1个月，可极大地刺激小梁骨和骨内膜骨形成，导致骨量显著增加。我们进一步在小鼠闭合性股骨骨折模型中测试了Wnt7b对骨愈合的影响。在骨折开始时诱导Wnt7b表达并不影响初始软骨形成，但促进了随后骨痂的矿化。因此，可探索将Wnt7b靶向递送至老龄骨骼或骨折部位作为一种潜在疗法。
