Centre for Bone and Arthritis Research at Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
J Leukoc Biol. 2018 Dec;104(6):1133-1145. doi: 10.1002/JLB.3A0318-094RR. Epub 2018 Jul 30.
Increased intake of vitamin A (retinoids) is associated with decreased bone mass and increased fracture risk in humans. Mechanistic studies in rodents have shown that hypervitaminosis A results in decreased bone mass caused by an increase in periosteal osteoclasts while simultaneously decreasing endocortic osteoclasts. In vivo and ex vivo bone organ cultures have demonstrated that excess retinoids increase osteoclast formation due to increased receptor activator of nuclear factor kappa B-ligand (RANKL) expression. In vitro, studies using murine bone marrow macrophages (BMM) have shown that retinoids inhibit osteoclast formation induced by recombinant RANKL. These opposing in vivo/ex vivo versus in vitro effects may elucidate why excess retinoids affect periosteal and endocortic osteoclast formation differently. In addition, it has been reported that retinoids can inhibit osteoclast formation under inflammatory conditions such as experimentally induced arthritis in mice. In the present study, we have compared the effect of all-trans-retinoic acid (ATRA) on physiologically and inflammatory induced osteoclastogenesis. ATRA inhibited physiologically induced (RANKL) osteoclast formation of human peripheral blood monocytes and mouse BMM as well as human monocytes stimulated with the pro-inflammatory compounds, TNF-α and LPS. The inhibition was due to impeded differentiation, rather than fusion, of mononucleated progenitor cells. ATRA disrupted differentiation by interfering with osteoclastogenic intracellular signaling. In line with this view, overexpression of Tnfrsf11a (encodes for RANK) in BMM could not overcome the inhibition of osteoclastogenesis by ATRA. The data suggest that ATRA inhibits both physiologic and inflammatory osteoclast differentiation of progenitors from the bone marrow and peripheral blood.
维生素 A（类视黄醇）摄入增加与人类骨量减少和骨折风险增加有关。啮齿动物的机制研究表明，高维生素 A 血症导致骨量减少，这是由于骨膜破骨细胞增加，同时减少了内皮质破骨细胞。体内和体外骨器官培养表明，过量的类视黄醇由于核因子 kappa B 受体激活物配体 (RANKL) 表达增加而增加破骨细胞形成。体外研究使用鼠骨髓巨噬细胞 (BMM) 表明，类视黄醇抑制由重组 RANKL 诱导的破骨细胞形成。这些体内/体外与体外相反的效应可能阐明为什么过量的类视黄醇会对骨膜和内皮质破骨细胞的形成产生不同的影响。此外，据报道，类视黄醇可以抑制炎症条件下的破骨细胞形成，如在小鼠实验性关节炎中。在本研究中，我们比较了全反式视黄酸 (ATRA) 对生理和炎症诱导的破骨细胞生成的影响。ATRA 抑制了人外周血单核细胞和鼠 BMM 的生理诱导 (RANKL) 破骨细胞形成，以及人单核细胞在促炎化合物 TNF-α 和 LPS 刺激下的破骨细胞形成。抑制是由于单核细胞祖细胞的分化受阻，而不是融合。ATRA 通过干扰破骨细胞生成的细胞内信号转导来破坏分化。与此一致的是，在 BMM 中转染 Tnfrsf11a（编码 RANK）的过表达不能克服 ATRA 对破骨细胞生成的抑制。数据表明，ATRA 抑制了骨髓和外周血祖细胞的生理和炎症性破骨细胞分化。
