Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany.
Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany.
Front Endocrinol (Lausanne). 2022 Sep 30;13:1016057. doi: 10.3389/fendo.2022.1016057. eCollection 2022.
In recent years, evidence has accumulated that the complement system, an integral part of innate immunity, may be involved in the regulation of bone homeostasis as well as inflammatory bone loss, for example, in rheumatoid arthritis and periodontitis. Complement may also contribute to osteoporosis development, but investigation of the mechanism is limited. Using mice with a conditional deletion of the complement anaphylatoxin receptor C5aR1, we here demonstrated that C5aR1 in osteoblasts ( mice) or osteoclasts ( mice) did not affect physiological bone turnover or age-related bone loss in either sex, as confirmed by micro-computed tomography, histomorphometry, and biomechanical analyses of the bone and by the measurement of bone turnover markers in the blood serum. When female mice were subjected to ovariectomy (OVX), a common model for postmenopausal osteoporosis, significant bone loss was induced in and mice, as demonstrated by a significantly reduced bone volume fraction, trabecular number and thickness as well as an increased trabecular separation in the trabecular bone compartment. Confirming this, the osteoclast number and the receptor activator of nuclear factor k-B (RANK) ligand (RANKL) serum level were significantly elevated in these mouse lines. By contrast, mice were protected from bone loss after OVX and the serum RANKL concentration was not increased after OVX. These data suggested that bone cell-specific C5aR1 may be redundant in bone homeostasis regulation under physiological conditions. However, C5aR1 on osteoblasts was crucial for the induction of bone resorption under osteoporotic conditions by stimulating RANKL release, whereas C5aR1 on osteoclasts did not regulate OVX-induced bone loss. Therefore, our results implicate C5aR1 on osteoblasts as a potential target for treating postmenopausal osteoporosis.
近年来，有证据表明补体系统作为固有免疫的一个组成部分，可能参与骨稳态的调节以及炎症性骨丢失，例如在类风湿关节炎和牙周炎中。补体也可能导致骨质疏松症的发展，但对其机制的研究还很有限。本研究使用条件性敲除补体过敏毒素受体 C5aR1 的小鼠，证明成骨细胞（ 小鼠）或破骨细胞（ 小鼠）中的 C5aR1 不会影响雌雄两性的生理骨转换或与年龄相关的骨丢失，这一点通过微计算机断层扫描、组织形态计量学以及骨生物力学分析，以及血清中骨转换标志物的测量得到了证实。当雌性小鼠接受卵巢切除术（OVX）时，会引起常见的绝经后骨质疏松症模型，在 或 小鼠中会引起明显的骨丢失，表现为骨体积分数、小梁数量和厚度显著降低以及小梁骨间隔增加。这一结果得到了证实，这些小鼠系中的破骨细胞数量和核因子 k-B 受体激活剂（RANK）配体（RANKL）血清水平显著升高。相比之下， 小鼠在 OVX 后免受骨丢失的影响，OVX 后血清 RANKL 浓度也没有增加。这些数据表明，在生理条件下，骨细胞特异性 C5aR1 可能在骨稳态调节中是多余的。然而，在骨质疏松症条件下，成骨细胞上的 C5aR1 通过刺激 RANKL 释放对于诱导骨吸收是至关重要的，而破骨细胞上的 C5aR1 并不调节 OVX 诱导的骨丢失。因此，我们的结果表明成骨细胞上的 C5aR1 可能是治疗绝经后骨质疏松症的潜在靶点。
