Department of Orthopedics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
Hospital for Special Surgery, New York, NY, USA.
J Biol Regul Homeost Agents. 2019 Jul-Aug;33(4):1105-1111.
The adapter protein myeloid differentiation primary response gene 88 (MyD88) links the intracellular domains of interleukin receptors 1 and 18, and most Toll-like receptors (TLRs) to interleukin 1 receptor associated kinase (IRAK) signaling and subsequent NF-κB-mediated transcription. Previous work showed that mice with global deficiency of MyD88 (MyD88) have osteopenic cancellous bone along with a reduction in osteoblastic but also osteoclastic surfaces. To further elucidate the role of MyD88 in bone, we utilized mice with osteoclast-restricted MyD88 expression in bone (MyD88). Bones of MyD88 and wild type (wt) mice were examined by microCT analysis. Mechanical properties of bones were tested by three-point bending, and gene expression measured using quantitative real-time polymerase chain reaction. In MyD88 mice, no osteopenic traits were observed, however, a drastic reduction in geometric parameters was detected. In trabecular bone a loss of connectivity density (-44%, p less than 0.0001) was measured and in cortical bone Imax (-31%, p less than 0.0001), Imin (-20%, p less than 0.001), J (-26%, p less than 0.0001) were reduced. Mechanical testing showed increased load to failure (77%, p less than 0.01) and decreased deflection at failure (-68%, p less than 0.01) of the femur. On the molecular level, relative gene expression analysis showed a (-29%, p less than 0.01) reduction in receptor activator of nuclear factor κ B ligand (RANKL) and no difference in osteoprotegerin (OPG) or RANK. Further, the bone resorption markers cathepsin K (CTSK) and tartrate-resistant acid phosphatase 5 (TRAP) were unchanged. In contrast, the bone formation markers collagen type 1 (COL1A1) and osteocalcin (OC) were decreased by -72% (p less than 0.0001) and -82% (p less than 0.0001), respectively. Together, our data suggests that the function of MyD88 in osteoclasts is sufficient to maintain bone mass, while it fails to preserve bone geometry, likely through dysfunctions in osteoblasts.
衔接蛋白髓样分化初级反应基因 88（MyD88）将白细胞介素受体 1 和 18 的细胞内结构域与白细胞介素 1 受体相关激酶（IRAK）信号转导和随后的 NF-κB 介导的转录联系起来。以前的工作表明，MyD88 全身性缺乏的小鼠（MyD88）的松质骨呈骨质疏松表现，同时成骨细胞和破骨细胞表面减少。为了进一步阐明 MyD88 在骨骼中的作用，我们利用骨骼中破骨细胞特异性表达 MyD88 的小鼠（MyD88）进行研究。使用 microCT 分析检测 MyD88 和野生型（wt）小鼠的骨骼。通过三点弯曲测试来检测骨骼的力学性能，并使用定量实时聚合酶链反应来测量基因表达。在 MyD88 小鼠中，未观察到骨质疏松特征，但检测到几何参数的急剧减少。在小梁骨中，检测到连接密度丧失（-44%，p＜0.0001），在皮质骨中，Imax（-31%，p＜0.0001）、Imin（-20%，p＜0.001）、J（-26%，p＜0.0001）减少。力学测试显示股骨的失效负载增加（77%，p＜0.01），失效挠度减少（-68%，p＜0.01）。在分子水平上，相对基因表达分析显示核因子 κ B 受体激活剂（RANKL）减少（-29%，p＜0.01），而骨保护素（OPG）或 RANK 无差异。此外，骨吸收标志物组织蛋白酶 K（CTSK）和抗酒石酸酸性磷酸酶 5（TRAP）没有变化。相反，骨形成标志物胶原 1 型（COL1A1）和骨钙素（OC）分别减少了-72%（p＜0.0001）和-82%（p＜0.0001）。总之，我们的数据表明，MyD88 在破骨细胞中的功能足以维持骨量，而不能维持骨几何形状，这可能是通过成骨细胞功能障碍引起的。
