Department of Treatment Center for Traumatic Injuries, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Province, China.
Division of Joint Surgery, Department of Orthopedics, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Province, China.
Aging (Albany NY). 2020 Nov 10;13(4):4976-4985. doi: 10.18632/aging.103717.
Osteogenic differentiation is critical to bone homeostasis, and its imbalance plays a key role in the progression of osteoporosis. Osteoblast cells are responsible for synthesizing new bone tissue, and understanding how to control osteoblastic differentiation is vital to the treatment of osteoporosis. Herein, we show that GPR173 signaling is involved in the regulation of osteoblastic differentiation in MC3T3-E1 cells. Our data reveals that GPR173 is abundantly expressed in MC3T3-E1 cells, and its expression is inducible upon the introduction of osteogenic media. The activation of GPR173 by its selective agonist phoenixin 20 induces the expression of several osteoblast signature genes including collagen type 1 alpha 1 (Col-I), osteocalcin (OCN), alkaline phosphatase (ALP) as well as increased matrix mineralization and ALP activity, suggesting that the activation of GPR173 promotes osteoblastic differentiation. Moreover, we show that the effect of phoenixin 20 is mediated by its induction on the key regulator runt-Related Transcription Factor 2 (Runx2). Mechanistically, we display that the action of phoenixin 20 requires the activation of MAPK kinase p38, and deactivation of p38 by its inhibitor SB203580 weakens the phoenixin 20-mediated induction of RUNX-2, ALP, and matrix mineralization. Silencing of GPR173 attenuates phoenixin 20-mediated osteoblastic differentiation, indicating its dependence on the receptor. Collectively, our study reveals a new role of GPR173 and its agonist phoenixin 20 in osteoblastic differentiation.
成骨分化对于骨内稳态至关重要，其失衡在骨质疏松症的进展中起着关键作用。成骨细胞负责合成新的骨组织，了解如何控制成骨细胞分化对于骨质疏松症的治疗至关重要。在此，我们表明 GPR173 信号参与调节 MC3T3-E1 细胞中的成骨细胞分化。我们的数据显示，GPR173 在 MC3T3-E1 细胞中大量表达，并且在引入成骨培养基时可诱导其表达。其选择性激动剂凤凰素 20 激活 GPR173 可诱导包括胶原类型 1 alpha 1（Col-I）、骨钙素（OCN）、碱性磷酸酶（ALP）在内的几种成骨细胞特征基因的表达，以及增加基质矿化和 ALP 活性，表明 GPR173 的激活促进成骨细胞分化。此外，我们表明凤凰素 20 的作用是通过其对关键调节因子 runt 相关转录因子 2（Runx2）的诱导介导的。在机制上，我们显示凤凰素 20 的作用需要 MAPK 激酶 p38 的激活，并且 p38 的抑制剂 SB203580 使其失活会削弱凤凰素 20 介导的 RUNX-2、ALP 和基质矿化的诱导。GPR173 的沉默减弱了凤凰素 20 介导的成骨细胞分化，表明其依赖于该受体。总之，我们的研究揭示了 GPR173 及其激动剂凤凰素 20 在成骨细胞分化中的新作用。
