Johns Hopkins Orthopaedics at Good Samaritan Hospital, Baltimore, MD, USA.
Bone. 2013 Apr;53(2):520-30. doi: 10.1016/j.bone.2013.01.009. Epub 2013 Jan 15.
The increased bone marrow lipid deposition in steroid-associated bone loss diseases indicates that abnormalities in fat metabolism are associated with disease development. Recent studies have suggested that bone marrow adipocytes are secretory cells and that they may release substances that have an inhibitory effect on the differentiation and function of osteoblasts. We hypothesized that exposure of bone-marrow-derived adipocytes to corticosteroids exacerbates their deleterious effects on osteoblast metabolism and function. Adipocytes and osteoblasts derived from a human mesenchymal stem cell line (240L) were co-cultured in the absence of direct cell contact with or without dexamethasone treatment. After 6days of co-culture, osteoblasts demonstrated significantly lower levels of function based on lower mineralization, alkaline phosphatase activity and expression of osteogenic (Runx2, osteocalcin) mRNA marker. Dexamethasone treatment resulted in significantly lower levels of osteoblastic function compared with co-cultured cells without dexamethasone. Furthermore, conditioned media from dexamethasone-treated adipocytes induced a similar toxic effect and increased apoptosis involving activation of caspases 3/7 compared with conditioned media without dexamethasone treatment. Within the conditioned media, a substantial increase in the levels of leptin and two saturated fatty acids (FAs; stearate and palmitate) was observed after dexamethasone treatment. Although leptin supplementation failed to induce the inhibitory effect on osteoblasts, similar toxic results were produced with stearate and palmitate treatment, and an increase in intracellular reactive oxygen species was observed. Stearate- and palmitate-induced apoptosis was blocked by a reactive oxygen species scavenger pyrrolidine dithiocarbamate. These data show that saturated FAs secreted from adipocytes induce lipotoxic effects via mechanisms that may involve reactive oxygen species accumulation in osteoblasts. Our results suggest that inhibition of saturated FA secretion would protect osteoblasts against adipocytes in corticosteroid-associated bone loss diseases.
在与类固醇相关的骨丢失疾病中，骨髓脂质沉积增加表明脂肪代谢异常与疾病的发展有关。最近的研究表明，骨髓脂肪细胞是分泌细胞，它们可能释放出对成骨细胞的分化和功能具有抑制作用的物质。我们假设，暴露于皮质类固醇的骨髓脂肪细胞会加剧其对成骨细胞代谢和功能的有害影响。将源自人间充质干细胞系（240L）的脂肪细胞和成骨细胞进行共培养，而无需直接细胞接触，并在有或没有地塞米松处理的情况下进行。在共培养 6 天后，成骨细胞的功能明显降低，表现为矿化程度、碱性磷酸酶活性和骨形成（Runx2、骨钙素）mRNA 标志物的表达降低。与没有地塞米松的共培养细胞相比，地塞米松处理导致成骨细胞的功能明显降低。此外，与没有地塞米松处理的条件培养基相比，来自地塞米松处理的脂肪细胞的条件培养基诱导了类似的毒性作用，并增加了涉及半胱天冬酶 3/7 激活的细胞凋亡。在条件培养基中，在经过地塞米松处理后观察到瘦素和两种饱和脂肪酸（硬脂酸和棕榈酸）的水平显著增加。尽管瘦素补充未能诱导对成骨细胞的抑制作用，但硬脂酸和棕榈酸处理产生了类似的毒性作用，并观察到细胞内活性氧物种的增加。通过使用活性氧物种清除剂吡咯烷二硫代氨基甲酸盐，阻断了硬脂酸和棕榈酸诱导的细胞凋亡。这些数据表明，脂肪细胞分泌的饱和脂肪酸通过可能涉及成骨细胞中活性氧物种积累的机制诱导脂肪毒性作用。我们的结果表明，抑制饱和 FA 的分泌将保护成骨细胞免受与皮质类固醇相关的骨丢失疾病中的脂肪细胞的影响。
