Shang Xinying, Hu Wei, Zhang Lin, Wei Rui
Department of Emergency Medicine, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, PR China.
Department of Cardiovascular Medicine, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, PR China.
Tissue Cell. 2025 Oct;96:103028. doi: 10.1016/j.tice.2025.103028. Epub 2025 Jun 25.
Osteoporosis (OP) is a systemic skeletal disease that contributes to compromised bone strength and increased fracture risk. This paper investigates the functional role of protein phosphatase 3 catalytic subunit α (PPP3CA) in OP and its mechanisms.
Bioinformatics prediction analysis was performed to identify genes associated with OP and its transcription factor. An OP mouse model was constructed by ovariectomy (OVX). RAW264.7 cells were induced to differentiate into osteoclasts using RANKL for in vitro experiments.
PPP3CA was poorly expressed in the femoral tissues of OVX-induced mice. Overexpression of PPP3CA reduced nuclear factor of activated T cells c1 (NFATC1) and matrix metalloproteinase 9 (MMP9) levels and the extent of extracellular signal-regulated protein kinase (ERK)1/2 phosphorylation. Overexpression of PPP3CA inhibited osteoclast differentiation and OP progression. Myc-associated zinc finger protein (MAZ) was highly expressed in the femoral tissues of OVX-induced mice and inhibited the transcription of PPP3CA by binding to its promoter. MAZ promoted the ERK/mitogen-activated protein kinase (MAPK) pathway and thus promoted osteoclastogenesis. Animal experiments further demonstrated that the MAZ/PPP3CA axis promoted osteoclastogenesis through the ERK/MAPK pathway in vivo.
MAZ promotes osteoclastogenesis and OP progression by activating the ERK/MAPK signaling pathway through transcriptional inhibition of PPP3CA. These findings not only elucidate a novel mechanism driving osteoclastogenesis but also highlight the MAZ/PPP3CA/ERK-MAPK axis as a promising target for innovative therapies aimed at curbing bone resorption and ultimately improving treatment outcomes in OP.
骨质疏松症（OP）是一种全身性骨骼疾病，会导致骨强度受损和骨折风险增加。本文研究蛋白磷酸酶3催化亚基α（PPP3CA）在OP中的功能作用及其机制。
进行生物信息学预测分析以鉴定与OP及其转录因子相关的基因。通过卵巢切除术（OVX）构建OP小鼠模型。使用RANKL诱导RAW264.7细胞分化为破骨细胞用于体外实验。
PPP3CA在OVX诱导的小鼠股骨组织中表达较低。PPP3CA的过表达降低了活化T细胞核因子c1（NFATC1）和基质金属蛋白酶9（MMP9）的水平以及细胞外信号调节蛋白激酶（ERK）1/2的磷酸化程度。PPP3CA的过表达抑制了破骨细胞分化和OP进展。Myc相关锌指蛋白（MAZ）在OVX诱导的小鼠股骨组织中高表达，并通过与PPP3CA启动子结合抑制其转录。MAZ促进ERK/丝裂原活化蛋白激酶（MAPK）途径，从而促进破骨细胞生成。动物实验进一步证明，MAZ/PPP3CA轴在体内通过ERK/MAPK途径促进破骨细胞生成。
MAZ通过转录抑制PPP3CA激活ERK/MAPK信号通路，促进破骨细胞生成和OP进展。这些发现不仅阐明了驱动破骨细胞生成的新机制，还突出了MAZ/PPP3CA/ERK-MAPK轴作为一种有前景的靶点，用于旨在抑制骨吸收并最终改善OP治疗效果的创新疗法。
