Chou Ya-Shuan, Chuang Shu-Chun, Chen Chung-Hwan, Ho Mei-Ling, Chang Je-Ken
Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
Front Cell Dev Biol. 2021 Aug 20;9:710664. doi: 10.3389/fcell.2021.710664. eCollection 2021.
Estrogen enhances long bone longitudinal growth during early puberty. Growth plate chondrocytes are the main cells that contribute to long bone elongation. The role of G-protein-coupled estrogen receptor-1 (GPER-1) in regulating growth plate chondrocyte function remains unclear. In the present study, we generated chondrocyte-specific GPER-1 knockout (CKO) mice to investigate the effect of GPER-1 in growth plate chondrocytes. In control mice, GPER-1 was highly expressed in the growth plates of 4- and 8-week-old mice, with a gradual decline through 12 to 16 weeks. In CKO mice, the GPER-1 expression in growth plate chondrocytes was significantly lower than that in the control mice (80% decrease). The CKO mice also showed a decrease in body length (crown-rump length), body weight, and the length of tibias and femurs at 8 weeks. More importantly, the cell number and thickness of the proliferative zone of the growth plate, as well as the thickness of primary spongiosa and length of metaphysis plus diaphysis in tibias of CKO mice, were significantly decreased compared with those of the control mice. Furthermore, there was also a considerable reduction in the number of proliferating cell nuclear antigens and Ki67-stained proliferating chondrocytes in the tibia growth plate in the CKO mice. The chondrocyte proliferation mediated by GPER-1 was further demonstrated treatment with a GPER-1 antagonist in cultured epiphyseal cartilage. This study demonstrates that GPER-1 positively regulates chondrocyte proliferation at the growth plate during early puberty and contributes to the longitudinal growth of long bones.
雌激素在青春期早期促进长骨纵向生长。生长板软骨细胞是促成长骨伸长的主要细胞。G蛋白偶联雌激素受体1（GPER-1）在调节生长板软骨细胞功能中的作用仍不清楚。在本研究中，我们构建了软骨细胞特异性GPER-1基因敲除（CKO）小鼠，以研究GPER-1在生长板软骨细胞中的作用。在对照小鼠中，GPER-1在4周龄和8周龄小鼠的生长板中高表达，在12至16周龄时逐渐下降。在CKO小鼠中，生长板软骨细胞中的GPER-1表达明显低于对照小鼠（降低80%）。CKO小鼠在8周龄时还表现出体长（顶臀长）、体重以及胫骨和股骨长度的减少。更重要的是，与对照小鼠相比，CKO小鼠生长板增殖区的细胞数量和厚度，以及胫骨初级松质骨的厚度和干骺端加骨干的长度均显著降低。此外，CKO小鼠胫骨生长板中增殖细胞核抗原和Ki67染色的增殖软骨细胞数量也有相当程度的减少。在培养的骨骺软骨中用GPER-1拮抗剂处理进一步证明了GPER-1介导的软骨细胞增殖。本研究表明，GPER-1在青春期早期对生长板软骨细胞增殖起正向调节作用，并促进长骨的纵向生长。
