Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
Institute for Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
J Bone Miner Res. 2022 Jan;37(1):137-151. doi: 10.1002/jbmr.4455. Epub 2021 Oct 21.
Mast cells are important tissue-resident sensor and effector immune cells but also play a major role in osteoporosis development. Mast cells are increased in numbers in the bone marrow of postmenopausal osteoporotic patients, and mast cell-deficient mice are protected from ovariectomy (OVX)-induced bone loss. In this study, we showed that mast cell-deficient Mcpt5-Cre R-DTA mice were protected from OVX-induced disturbed fracture healing, indicating a critical role for mast cells in the pathomechanisms of impaired bone repair under estrogen-deficient conditions. We revealed that mast cells trigger the fracture-induced inflammatory response by releasing inflammatory mediators, including interleukin-6, midkine (Mdk), and C-X-C motif chemokine ligand 10 (CXCL10), and promote neutrophil infiltration into the fracture site in OVX mice. Furthermore, mast cells were responsible for reduced osteoblast and increased osteoclast activities in OVX mice callus, as well as increased receptor activator of NF-κB ligand serum levels in OVX mice. Additional in vitro studies with human cells showed that mast cells stimulate osteoclastogenesis by releasing the osteoclastogenic mediators Mdk and CXCL10 in an estrogen-dependent manner, which was mediated via the estrogen receptor alpha on mast cells. In conclusion, mast cells negatively affect the healing of bone fractures under estrogen-deficient conditions. Hence, targeting mast cells might provide a therapeutic strategy to improve disturbed bone repair in postmenopausal osteoporosis. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
肥大细胞是重要的组织驻留传感器和效应免疫细胞，但在骨质疏松症的发展中也起着主要作用。绝经后骨质疏松症患者的骨髓中肥大细胞数量增加，而缺乏肥大细胞的小鼠对卵巢切除术（OVX）引起的骨丢失具有保护作用。在这项研究中，我们表明，缺乏肥大细胞的 Mcpt5-Cre R-DTA 小鼠对 OVX 引起的骨折愈合障碍具有保护作用，表明肥大细胞在雌激素缺乏条件下受损骨修复的病理机制中起关键作用。我们揭示了肥大细胞通过释放炎症介质（包括白细胞介素 6、中期因子（Mdk）和 C-X-C 基序趋化因子配体 10（CXCL10））触发骨折引起的炎症反应，并促进中性粒细胞浸润到 OVX 小鼠的骨折部位。此外，肥大细胞负责减少 OVX 小鼠骨痂中的成骨细胞和增加破骨细胞活性，以及增加 OVX 小鼠血清中 NF-κB 配体受体激活剂的水平。对人类细胞的额外体外研究表明，肥大细胞通过以雌激素依赖的方式释放破骨细胞生成介质 Mdk 和 CXCL10 来刺激破骨细胞生成，这是通过肥大细胞上的雌激素受体α介导的。总之，肥大细胞在雌激素缺乏条件下对骨折愈合产生负面影响。因此，针对肥大细胞可能为改善绝经后骨质疏松症中受损的骨修复提供一种治疗策略。
