Chang Shun-Fu, Hsieh Rong-Ze, Huang Kuo-Chin, Chang Cheng Allen, Chiu Fang-Yao, Kuo Hsing-Chun, Chen Cheng-Nan, Su Yu-Ping
Department of Medical Research and Development, Chang Gung Memorial Hospital Chiayi Branch, Chiayi, Taiwan.
Department of Orthopaedics, Chang Gung Memorial Hospital Chiayi Branch, Chiayi, Taiwan.
PLoS One. 2015 Dec 4;10(12):e0144252. doi: 10.1371/journal.pone.0144252. eCollection 2015.
Bone morphogenetic proteins (BMPs) play positive roles in cartilage development, but they can barely be detected in healthy articular cartilage. However, recent evidence has indicated that BMPs could be detected in osteoarthritic and damaged cartilage and their precise roles have not been well defined. Extremely high amounts of leptin have been reported in obese individuals, which can be associated with osteoarthritis (OA) development. The aim of this study was to investigate whether BMPs could be induced in human primary chondrocytes during leptin-stimulated OA development and the underlying mechanism. We found that expression of BMP-2 mRNA, but not BMP-4, BMP-6, or BMP-7 mRNA, could be increased in human primary chondrocytes under leptin stimulation. Moreover, this BMP-2 induction was mediated through transcription factor-signal transducer and activator of transcription (STAT) 3 activation via JAK2-ERK1/2-induced Ser727-phosphorylation. Of note, histone deacetylases (HDACs) 3 and 4 were both involved in modulating leptin-induced BMP-2 mRNA expression through different pathways: HDAC3, but not HDAC4, associated with STAT3 to form a complex. Our results further demonstrated that the role of BMP-2 induction under leptin stimulation is to increase collagen II expression. The findings in this study provide new insights into the regulatory mechanism of BMP-2 induction in leptin-stimulated chondrocytes and suggest that BMP-2 may play a reparative role in regulating leptin-induced OA development.
骨形态发生蛋白（BMPs）在软骨发育中发挥着积极作用，但在健康的关节软骨中几乎检测不到。然而，最近的证据表明，在骨关节炎和受损软骨中可以检测到BMPs，但其确切作用尚未明确。据报道，肥胖个体中瘦素含量极高，这可能与骨关节炎（OA）的发展有关。本研究的目的是探讨在瘦素刺激的OA发展过程中，人原代软骨细胞中是否能诱导产生BMPs及其潜在机制。我们发现，在瘦素刺激下，人原代软骨细胞中BMP-2 mRNA的表达会增加，而BMP-4、BMP-6或BMP-7 mRNA的表达则不会增加。此外，这种BMP-2的诱导是通过转录因子信号转导和转录激活因子（STAT）3的激活介导的，该激活是由JAK2-ERK1/2诱导的Ser727磷酸化实现的。值得注意的是，组蛋白去乙酰化酶（HDACs）3和4都通过不同途径参与调节瘦素诱导的BMP-2 mRNA表达：HDAC3而非HDAC4与STAT3结合形成复合物。我们的结果进一步证明，瘦素刺激下诱导产生BMP-2的作用是增加Ⅱ型胶原蛋白的表达。本研究结果为瘦素刺激的软骨细胞中BMP-2诱导的调控机制提供了新的见解，并表明BMP-2可能在调节瘦素诱导的OA发展中发挥修复作用。
