肥大性骨关节病（厚皮骨膜增生症），是以杵状指、长骨骨膜增生和脸面皮肤增厚为特征的属于骨硬化症一类疾病，按病因不同分为原发性和继发性。我们于2012年在国际上首先报告了编码前列腺素转运蛋白的SLCO2A1基因纯合突变导致原发性肥大性骨关节病，后被OMIM命名为常隐2型，结合国外报告的1型是由编码PGE2降解酶基因(HPGD)突变引起，至此基本阐明了原发性肥大性骨关节病是PGE2降解减少而发病。但随着近年我们对常隐2型临床病例的积累，发现该型患者均是青春期发病的男性，而女性则在绝经后发病且症状轻微，显然发病存在显著性别差异，强烈提示性腺激素调节PGE2的转运和降解，但机制尚未阐明。本项目拟利用目前已基本建立的SLCO2A1突变敲入小鼠模型，予性腺激素剥夺和替代干预等，从细胞、分子和整体水平以明确本病发生中性激素对PGE2代谢之确切影响及机制，不但解决困惑临床多年之问题，而且对其防治具有重大意义

Hypertrophic osteoarthropathy, also known as primary or secondary pachydermoperiostosis, belongs to osteosclerosis featured by digital clubbing, periostosis and pachydermia. In 2012, we first reported that primary hypertrophic osteoarthropathy (PHO) is caused by homozygous mutations in SLCO2A1gene coding the prostaglandin transporter. Therefore, the finding was named as autosomal recessive type 2 (PHOAR2）by Online Mendelian Inheritance in Man (OMIM 614441). Combining foreign report autosomal recessive type 1(PHOAR1) caused by HPGD gene coding hydroxyprostaglandin dehydrogenase 15-(NAD) (OMIM259100), the metabolic disturbance of PGE2 causing reduced degradation was underlying the pathogenesis of PHO. However, with dozens of PHOAR2 patients molecularly diagnosed, a significant age and gender bias has been noted: the onset typically occurs at puberty of males and postmenopause of females with lower ratio and more mild symptoms compared to that of males, and it is absent in PHOAR1. These considerable findings strongly indicate the crucial role of sex hormones in PGE2 transportation. However, the mechanism remained unknown so far. Our study intends to utilize the SLCO2A1 mutation knock-in mouse model basically established at present for depletion and replacement interventions of sex hormones, and clarify the exact impact and mechanism of sex hormones on PGE2 metabolism at the molecular, cell, and in vivo levels in the pathogenesis of primary PHO, which not only solve the problem of confused clinically for many years, but also for the prevention and treatment of PHO is of great significance.