Department of Orthopaedics, Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
Department of Orthopaedics, Case Western Reserve University, Cleveland, OH 44106, USA.
Bone. 2021 Feb;143:115733. doi: 10.1016/j.bone.2020.115733. Epub 2020 Nov 4.
Jab1, also known as Csn5/Cops5, is a key subunit of the COP9 Signalosome, a highly conserved macromolecular complex. We previously reported that the conditional knockout of Jab1 in mouse limb buds and chondrocytes results in severely shortened limbs and neonatal lethal chondrodysplasia, respectively. In this study, we further investigated the specific role of Jab1 in osteoblast differentiation and postnatal bone growth by characterizing a novel mouse model, the Osx-cre; Jab1 conditional knockout (Jab1 cKO) mouse, in which Jab1 is deleted in osteoblast precursor cells. Jab1 cKO mutant mice appeared normal at birth, but developed progressive dwarfism. Inevitably, all mutant mice died prior to weaning age. The histological and micro-computed tomography analysis of mutant long bones revealed severely altered bone microarchitecture, with a significant reduction in trabecular thickness. Moreover, Jab1 cKO mouse tibiae had a drastic decrease in mineralization near the epiphyseal growth plates, and Jab1 cKO mice also developed spontaneous fractures near the tibiofibular junction. Additionally, our cell culture studies demonstrated that Jab1 deletion in osteoblast precursors led to decreased mineralization and a reduced response to TGFβ and BMP signaling. Moreover, an unbiased reporter screen also identified decreased TGFβ activity in Jab1-knockdown osteoblasts. Thus, Jab1 is necessary for proper osteoblast differentiation and postnatal bone growth, likely in part through its positive regulation of the TGFβ and BMP signaling pathways in osteoblast progenitor cells.
Jab1，也被称为 Csn5/Cops5，是 COP9 信号小体的关键亚基，COP9 信号小体是一种高度保守的大分子复合物。我们之前的研究报道了条件性敲除 Jab1 分别导致小鼠肢芽和软骨细胞中严重缩短的肢体和新生儿致命性软骨发育不良。在这项研究中，我们通过对一种新型的小鼠模型（Osx-cre; Jab1 条件性敲除（Jab1 cKO）小鼠）进行了进一步的研究，该模型中 Jab1 在成骨前体细胞中被删除，从而进一步研究了 Jab1 在成骨细胞分化和出生后骨骼生长中的特定作用。Jab1 cKO 突变小鼠在出生时看起来正常，但出现进行性侏儒症。不可避免的是，所有突变小鼠都在断奶前死亡。对突变长骨的组织学和微计算机断层扫描分析显示，骨微观结构严重改变，骨小梁厚度显著减少。此外，Jab1 cKO 小鼠的骺板附近的矿化程度明显降低，Jab1 cKO 小鼠在胫腓骨连接处也发生自发性骨折。此外，我们的细胞培养研究表明，成骨前体细胞中 Jab1 的缺失导致矿化减少以及对 TGFβ 和 BMP 信号的反应减弱。此外，一项无偏倚的报告基因筛选还发现 Jab1 敲低的成骨细胞中 TGFβ 活性降低。因此，Jab1 对于成骨细胞的正常分化和出生后骨骼生长是必要的，这可能部分是通过其对成骨前体细胞中 TGFβ 和 BMP 信号通路的正向调节作用。
