Department of Spine Surgery and Musculoskeletal Tumor, Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
College of Life Sciences, Wuhan University, Wuhan 430072, China.
Oxid Med Cell Longev. 2021 Nov 15;2021:2896674. doi: 10.1155/2021/2896674. eCollection 2021.
Bone resorption diseases, including osteoporosis, are usually caused by excessive osteoclastogenesis. Unc-51-like autophagy activating kinase 1 (ULK1), a mammalian serine/threonine kinase, may participate in the regulation of bone homeostasis and osteolytic metastasis. In this study, ULK1 expression during osteoclastogenesis was detected with RT-PCR. We knocked down or overexpressed ULK1 through siRNA or lentiviral transduction in bone marrow macrophage (BMM). TRAP and phalloidin staining were performed to detect the osteoclastogenesis activity. Ovariectomized (OVX) mouse model of osteoporosis and a mouse of model osteoclast-induced bone resorption were applied to explore the role of ULK1 in bone resorption in vivo. The results showed that ULK1 expression was downregulated during osteoclast differentiation and was clinically associated with osteoporosis. ULK1 inhibited osteoclast differentiation in vitro. Knockdown of ULK1 expression activated phosphorylation of c-Jun N-terminal kinase (JNK) and spleen tyrosine kinase (Syk). Docking protein 3 (DOK3) was coexpressed with ULK1 during osteoclastogenesis. Downregulation of DOK3 offsets the effect of ULK1 on osteoclastogenesis and induced phosphorylation of JNK and Syk. Activation of ULK1 impeded bone loss in OVX mice with osteoporosis. Additionally, upregulation of ULK1 inhibited osteoclast-induced bone resorption in vivo. Therefore, our study reveals a novel ULK1/DOK3/Syk axis that regulates osteoclast differentiation and bone resorption, and targeting ULK1 is a potential therapeutic strategy for osteoporosis.
骨吸收疾病，包括骨质疏松症，通常是由破骨细胞过度生成引起的。非典型卷曲相关激酶 1（ULK1）是一种哺乳动物丝氨酸/苏氨酸激酶，可能参与骨稳态和溶骨性转移的调节。在本研究中，通过 RT-PCR 检测 ULK1 在破骨细胞生成过程中的表达。我们通过 siRNA 或慢病毒转导在骨髓巨噬细胞（BMM）中敲低或过表达 ULK1。通过 TRAP 和鬼笔环肽染色检测破骨细胞生成活性。应用去卵巢（OVX）骨质疏松症小鼠模型和模型破骨细胞诱导的骨吸收小鼠模型，探讨 ULK1 在体内骨吸收中的作用。结果表明，ULK1 表达在破骨细胞分化过程中下调，并与骨质疏松症临床相关。ULK1 在体外抑制破骨细胞分化。敲低 ULK1 表达激活了 c-Jun N-末端激酶（JNK）和脾酪氨酸激酶（Syk）的磷酸化。在破骨细胞生成过程中，衔接蛋白 3（DOK3）与 ULK1 共表达。下调 DOK3 抵消了 ULK1 对破骨细胞生成的影响，并诱导 JNK 和 Syk 的磷酸化。ULK1 的激活阻止了骨质疏松症 OVX 小鼠的骨丢失。此外，ULK1 的上调抑制了体内破骨细胞诱导的骨吸收。因此，本研究揭示了一个新的 ULK1/DOK3/Syk 轴，调节破骨细胞分化和骨吸收，靶向 ULK1 是骨质疏松症的一种潜在治疗策略。
