Abstract：
Missense variants in the MBTPS2 gene, located on the X chromosome, have been associated with an X-linked recessive form of osteogenesis imperfecta (X-OI), an inherited bone dysplasia characterized by multiple and recurrent bone fractures, short stature, and various skeletal deformities in affected individuals. The role of site-2 protease, encoded by MBTPS2, and the molecular pathomechanism underlying the disease are to date elusive. This study is the first to report on the generation of two Mbtps2 mouse models, a knock-in mouse carrying one of the disease-causative MBTPS2 variants (N455S) and a Mbtps2 knock-out (ko) mouse. Because both loss-of-function variants lead to embryonic lethality in hemizygous male mutant mice, we performed a comprehensive skeletal analysis of heterozygous Mbtps2+/N455S and Mbtps2+/ko female mice. Both models displayed osteochondral abnormalities such as thinned subchondral bone, altered subchondral osteocyte interconnectivity as well as thickened articular cartilage with chondrocyte clustering, altogether resembling an early osteoarthritis (OA) phenotype. However, distant from the joints, no alterations in the bone mass and turnover could be detected in either of the mutant mice. Based on our findings we conclude that MBTPS2 haploinsufficiency results in early OA-like alterations in the articular cartilage and underlying subchondral bone, which likely precede the development of typical OI phenotype in bone. Our study provides first evidence for a potential role of site-2 protease for maintaining homeostasis of both bone and cartilage.
摘要：
MBTPS2基因的错义变异，位于X染色体上，与X连锁隐性形式的成骨不全症（X-OI）有关，以多发性和复发性骨折为特征的遗传性骨发育不良，身材矮小,以及受影响个体的各种骨骼畸形。位点2蛋白酶的作用，由MBTPS2编码，迄今为止，该疾病背后的分子病理机制难以捉摸。本研究首次报道了两种X-OI小鼠模型的产生，携带一种致病MBTPS2变体（N455S）的敲入小鼠和Mbtps2敲除（ko）小鼠。因为这两种功能丧失变异导致半合子雄性突变小鼠的胚胎致死性，我们对杂合Mbtps2+/N455S和Mbtps2+/ko雌性小鼠进行了综合骨骼分析。两种模型都显示骨软骨异常，例如软骨下骨变薄，软骨下骨细胞的相互连接性改变以及软骨细胞聚集的关节软骨增厚，完全类似于早期骨关节炎（OA）表型。然而,远离关节，在任一突变小鼠中均未检测到骨量和更新的改变。根据我们的发现，我们得出结论，MBTPS2单倍功能不全导致关节软骨和潜在的软骨下骨的早期OA样改变。这可能先于骨骼中典型的OI表型的发展。我们的研究为位点2蛋白酶在维持骨骼和软骨稳态方面的潜在作用提供了第一个证据。
