Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.
Bone Biology and Disease Laboratory, School of Biomedical Sciences, The University of Western Australia, Nedlands, Western Australia, Australia.
J Bone Miner Res. 2021 Nov;36(11):2214-2228. doi: 10.1002/jbmr.4413. Epub 2021 Aug 3.
Osteal macrophages (osteomacs) support osteoblast function and promote bone anabolism, but their contribution to osteoporosis has not been explored. Although mouse ovariectomy (OVX) models have been repeatedly used, variation in strain, experimental design and assessment modalities have contributed to no single model being confirmed as comprehensively replicating the full gamut of osteoporosis pathological manifestations. We validated an OVX model in adult C3H/HeJ mice and demonstrated that it presents with human postmenopausal osteoporosis features with reduced bone volume in axial and appendicular bone and bone loss in both trabecular and cortical bone including increased cortical porosity. Bone loss was associated with increased osteoclasts on trabecular and endocortical bone and decreased osteoblasts on trabecular bone. Importantly, this OVX model was characterized by delayed fracture healing. Using this validated model, we demonstrated that osteomacs are increased post-OVX on both trabecular and endocortical bone. Dual F4/80 (pan-macrophage marker) and tartrate-resistant acid phosphatase (TRAP) staining revealed osteomacs frequently located near TRAP osteoclasts and contained TRAP intracellular vesicles. Using an in vivo inducible macrophage depletion model that does not simultaneously deplete osteoclasts, we observed that osteomac loss was associated with elevated extracellular TRAP in bone marrow interstitium and increased serum TRAP. Using in vitro high-resolution confocal imaging of mixed osteoclast-macrophage cultures on bone substrate, we observed macrophages juxtaposed to osteoclast basolateral functional secretory domains scavenging degraded bone byproducts. These data demonstrate a role for osteomacs in supporting osteoclastic bone resorption through phagocytosis and sequestration of resorption byproducts. Overall, our data expose a novel role for osteomacs in supporting osteoclast function and provide the first evidence of their involvement in osteoporosis pathogenesis. © 2021 American Society for Bone and Mineral Research (ASBMR).
成骨细胞巨噬细胞（osteomacs）支持成骨细胞的功能并促进骨合成代谢，但它们在骨质疏松症中的作用尚未被探索。尽管已经反复使用了小鼠卵巢切除术（OVX）模型，但由于品系、实验设计和评估方式的差异，没有一种模型被证实能够全面复制骨质疏松症所有病理表现。我们在成年 C3H/HeJ 小鼠中验证了 OVX 模型，并证明其具有人类绝经后骨质疏松症的特征，表现为轴向和附肢骨的骨量减少，以及小梁骨和皮质骨的骨丢失，包括皮质骨孔隙度增加。骨丢失与小梁骨和内皮质骨上破骨细胞的增加以及小梁骨上成骨细胞的减少有关。重要的是，这种 OVX 模型的特点是骨折愈合延迟。使用这种经过验证的模型，我们证明了 OVX 后在小梁骨和内皮质骨上成骨细胞巨噬细胞增多。双重 F4/80（泛巨噬细胞标志物）和抗酒石酸酸性磷酸酶（TRAP）染色显示成骨细胞巨噬细胞经常位于 TRAP 破骨细胞附近，并含有 TRAP 细胞内小泡。使用一种不会同时耗尽破骨细胞的体内诱导性巨噬细胞耗竭模型，我们观察到成骨细胞巨噬细胞耗竭与骨髓间质中细胞外 TRAP 升高和血清 TRAP 升高有关。通过在骨基质上进行混合破骨细胞-巨噬细胞培养的体外高分辨率共聚焦成像，我们观察到巨噬细胞与破骨细胞基底外侧功能分泌区并列，通过吞噬和隔离吸收产物来清除降解的骨。这些数据表明成骨细胞巨噬细胞在通过吞噬作用和隔离吸收产物来支持破骨细胞骨吸收方面发挥作用。总的来说，我们的数据揭示了成骨细胞巨噬细胞在支持破骨细胞功能中的新作用，并为它们参与骨质疏松症发病机制提供了第一个证据。
