Department of Orthopaedic, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pujian Road, Shanghai, 200127, China.
Cell Biol Int. 2018 Feb;42(2):169-179. doi: 10.1002/cbin.10882. Epub 2017 Nov 9.
Longitudinal bone growth is governed by a complex network of endocrine signals including leptin. In mouse, leptin deficiency leads to distinct phenotypes in bones of the limb and spine, suggesting the appendicular and axial skeletons are subject to differential regulation by leptin. We established primary cultures for the chondrocytes from tibial and vertebral epiphyseal plates. Cellular proliferation and apoptosis were analyzed for the chondrocytes that had been treated with various concentrations of leptin. Crucial factors for chondrocyte proliferation and differentiation, such as BMP7 and Wnt3, were measured in the cells treated with leptin alone or in combination with pharmacological inhibitors of STAT and ERK signaling pathways. Primary culture of tibial epiphyseal plate chondrocytes has greater proliferating capability compared with that of vertebral epiphyseal plate chondrocytes. Leptin could promote the proliferation of tibial epiphyseal plate chondrocytes, while its effect on vertebral epiphyseal plate chondrocytes was inhibitory. Consistently, apoptosis is inhibited in tibial but promoted in vertebral epiphyseal plate chondrocytes by leptin. Importantly, leptin differentially modulates chondrogenic signaling pathways in tibial and vertebral epiphyseal chondrocytes through STAT and ERK pathways. Leptin differentially regulates chondrogenic proliferation and differentiation in appendicular and axial regions of the skeletons. The signaling pathways in these two regions are also distinct and subject to differential regulation by leptin through the STAT pathway in tibial epiphyseal plate chondrocytes but through the ERK pathway in vertebral epiphyseal plate chondrocytes. Therefore, the regulation of leptin is multi-faceted in the distinct anatomical regions of the skeleton. Knowledge gained from this system will provide insights into the pathophysiological causes for the diseases related to bone development and metabolism.
骨的纵向生长受包括瘦素在内的复杂内分泌信号网络调控。在小鼠中，瘦素缺乏导致四肢和脊柱骨骼出现明显表型，提示附肢和脊柱骨骼受到瘦素的差异调控。我们建立了来自胫骨和椎体骺板的软骨细胞原代培养。用不同浓度的瘦素处理软骨细胞后，分析其细胞增殖和凋亡。在单独用瘦素或与 STAT 和 ERK 信号通路的药理学抑制剂联合处理的细胞中，测量了软骨细胞增殖和分化的关键因子，如 BMP7 和 Wnt3。与椎体骺板软骨细胞相比，胫骨骺板软骨细胞的增殖能力更强。瘦素可促进胫骨骺板软骨细胞增殖，而对椎体骺板软骨细胞的作用则具有抑制性。同样，瘦素抑制胫骨骺板软骨细胞凋亡，而促进椎体骺板软骨细胞凋亡。重要的是，瘦素通过 STAT 和 ERK 通路，在胫骨和椎体骺板软骨细胞中差异调节软骨生成信号通路。瘦素在附肢和脊柱骨骼的附肢区域中差异调节软骨生成的增殖和分化。这两个区域的信号通路也不同，通过胫骨骺板软骨细胞中的 STAT 通路，而通过椎体骺板软骨细胞中的 ERK 通路，瘦素对其进行差异调控。因此，瘦素在骨骼的不同解剖区域的调节是多方面的。从该系统获得的知识将为与骨骼发育和代谢相关疾病的病理生理原因提供深入了解。
