Uehara Shunsuke, Udagawa Nobuyuki, Kobayashi Yasuhiro
Department of Biochemistry, Matsumoto Dental University, Nagano, 399-0781, Japan.
Department of Biochemistry, Matsumoto Dental University, Nagano, 399-0781, Japan; Institute for Oral Science, Matsumoto Dental University, Nagano, 399-0781, Japan.
J Oral Biosci. 2019 Sep;61(3):135-140. doi: 10.1016/j.job.2019.07.002. Epub 2019 Aug 7.
Wnt signaling pathways are largely divided into the β-catenin-dependent canonical pathway and β-catenin-independent non-canonical pathways. The roles of Wnt signaling in bone metabolism have been extensively investigated. We previously attempted to clarify the roles of Wnt-non-canonical signaling in bone resorption and demonstrated that Wnt5a-receptor tyrosine kinase-like orphan receptor 2 (Ror2) signaling promoted osteoclast differentiation by enhancing RANK expression in osteoclast precursor cells. However, the roles of Wnt5a-Ror2 signaling in osteoclast function remain unclear.
Trabecular bone mass was significantly greater in osteoclast-specific Ror2-deficient (Ror2) mice than in control mice due to the decreased bone-resorbing activity of osteoclasts. Wnt5a-Ror2 signaling activated Rho in osteoclasts via dishevelled-associated activator of morphogenesis 2 (Daam2). The expression of protein kinase N3 (Pkn3), a Rho effector, increased during osteoclast differentiation. Trabecular bone mass was significantly greater in Pkn3-deficient mice than in wild-type mice due to the decreased bone-resorbing activity of osteoclasts. Pkn3 bound to c-Src and Pyk2 in a Wnt5a-Ror2 signaling-dependent manner, thereby enhancing the kinase activity of c-Src in osteoclasts. The binding of Pkn3 to c-Src was essential for the bone-resorbing activity of osteoclasts.
Wnt5a-Ror2 signaling promotes the bone-resorbing activity of osteoclasts by activating the Daam2-Rho-Pkn3-c-Src pathways. Pkn3 inhibitors, therefore, have potential as therapeutic agents for osteoporosis and bone destruction in inflammatory diseases.
Wnt信号通路主要分为依赖β-连环蛋白的经典通路和不依赖β-连环蛋白的非经典通路。Wnt信号在骨代谢中的作用已得到广泛研究。我们之前试图阐明Wnt非经典信号在骨吸收中的作用，并证明Wnt5a-受体酪氨酸激酶样孤儿受体2（Ror2）信号通过增强破骨细胞前体细胞中RANK的表达来促进破骨细胞分化。然而，Wnt5a-Ror2信号在破骨细胞功能中的作用仍不清楚。
由于破骨细胞的骨吸收活性降低，破骨细胞特异性Ror2缺陷（Ror2）小鼠的小梁骨量显著高于对照小鼠。Wnt5a-Ror2信号通过形态发生相关的散乱蛋白激活剂2（Daam2）在破骨细胞中激活Rho。Rho效应蛋白蛋白激酶N3（Pkn3）的表达在破骨细胞分化过程中增加。由于破骨细胞的骨吸收活性降低，Pkn3缺陷小鼠的小梁骨量显著高于野生型小鼠。Pkn3以Wnt5a-Ror2信号依赖的方式与c-Src和Pyk2结合，从而增强破骨细胞中c-Src的激酶活性。Pkn3与c-Src的结合对破骨细胞的骨吸收活性至关重要。
Wnt5a-Ror2信号通过激活Daam2-Rho-Pkn3-c-Src通路促进破骨细胞的骨吸收活性。因此，Pkn3抑制剂有潜力作为治疗骨质疏松症和炎症性疾病中骨破坏的治疗药物。
