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BACKGROUND

Mesenchymal stem cells (MSC) of bone marrow are the progenitor of osteoblasts and adipocytes. MSC tend to differentiate into adipocytes, instead of osteoblasts, with aging. This favors the loss of bone mass and development of osteoporosis. Hypoxia induces hypoxia inducible factor 1α gene encoding transcription factor, which regulates the expression of genes related to energy metabolism and angiogenesis. That allows a better adaptation to low O conditions. Sustained hypoxia has negative effects on bone metabolism, favoring bone resorption. Yet, surprisingly, cyclic hypoxia (CH), short times of hypoxia followed by long times in normoxia, can modulate MSC differentiation and improve bone health in aging.

AIM

To evaluate the CH effect on MSC differentiation, and whether it improves bone mineral density in elderly.

METHODS

MSC cultures were induced to differentiate into osteoblasts or adipocytes, in CH (3% O for 1, 2 or 4 h, 4 d a week). Extracellular-matrix mineralization and lipid-droplet formation were studied in MSC induced to differentiate into osteoblast or adipocytes, respectively. In addition, gene expression of marker genes, for osteogenesis or adipogenesis, have been quantified by quantitative real time polymerase chain reaction. The studies with elderly (> 75 years old; = 10) were carried out in a hypoxia chamber, simulating an altitude of 2500 m above sea level, or in normoxia, for 18 wk (36 CH sessions of 16 min each). Percentages of fat mass and bone mineral density from whole body, trunk and right proximal femur (femoral, femoral neck and trochanter) were assessed, using dual-energy X-ray absorptiometry.

RESULTS

CH (4 h of hypoxic exposure) inhibited extracellular matrix mineralization and lipid-droplet formation in MSC induced to differentiate into osteoblasts or adipocytes, respectively. However, both parameters were not significantly affected by the other shorter hypoxia times assessed. The longest periods of hypoxia downregulated the expression of genes related to extracellular matrix formation, in MSC induced to differentiate into osteoblasts. Interestingly, osteocalcin (associated to energy metabolism) was upregulated. Vascular endothelial growth factor an expression and low-density lipoprotein receptor related protein 5/6/dickkopf Wnt signaling pathway inhibitor 1 (associated to Wnt/β-catenin pathway activation) increased in osteoblasts. Yet, they decreased in adipocytes after CH treatments, mainly with the longest hypoxia times. However, the same CH treatments increased the osteoprotegerin/receptor activator for nuclear factor kappa B ligand ratio in both cell types. An increase in total bone mineral density was observed in elderly people exposed to CH, but not in specific regions. The percentage of fat did not vary between groups.

CONCLUSION

CH may have positive effects on bone health in the elderly, due to its possible inhibitory effect on bone resorption, by increasing the osteoprotegerin / receptor activator for nuclear factor kappa B ligand ratio.

BACKGROUND

AIM

To evaluate the CH effect on MSC differentiation, and whether it improves bone mineral density in elderly.

METHODS

RESULTS

CONCLUSION

背景

骨髓间充质干细胞（MSC）是成骨细胞和脂肪细胞的祖细胞。随着衰老，MSC倾向于分化为脂肪细胞而非成骨细胞。这有利于骨量流失和骨质疏松症的发展。缺氧诱导编码转录因子的缺氧诱导因子1α基因，该基因调节与能量代谢和血管生成相关的基因表达。这使得细胞能更好地适应低氧环境。持续缺氧对骨代谢有负面影响，促进骨吸收。然而，令人惊讶的是，周期性缺氧（CH），即短时间缺氧后长时间处于常氧状态，可调节MSC分化并改善衰老过程中的骨骼健康。

目的

评估CH对MSC分化的影响，以及它是否能改善老年人的骨密度。

方法

将MSC培养物诱导分化为成骨细胞或脂肪细胞，采用CH（每周4天，3%氧气浓度，分别暴露1、2或4小时）。分别研究诱导分化为成骨细胞或脂肪细胞的MSC中的细胞外基质矿化和脂滴形成。此外，通过定量实时聚合酶链反应对成骨或成脂标记基因的表达进行定量。对老年受试者（>75岁；n = 10）的研究在模拟海拔2500米的缺氧舱中或常氧环境下进行18周（共36次CH，每次16分钟）。使用双能X线吸收法评估全身、躯干和右股骨近端（股骨、股骨颈和转子）的脂肪量百分比和骨密度。

结果

CH（4小时缺氧暴露）分别抑制了诱导分化为成骨细胞或脂肪细胞的MSC中的细胞外基质矿化和脂滴形成。然而，其他较短的缺氧时间对这两个参数没有显著影响。最长的缺氧时间下调了诱导分化为成骨细胞的MSC中与细胞外基质形成相关基因的表达。有趣的是，骨钙素（与能量代谢相关）上调。成骨细胞中血管内皮生长因子表达以及低密度脂蛋白受体相关蛋白5/6/ dickkopf Wnt信号通路抑制剂1（与Wnt/β-连环蛋白通路激活相关）增加。然而，CH处理后脂肪细胞中的这些因子减少，主要是在最长缺氧时间时。然而，相同的CH处理增加了两种细胞类型中骨保护素/核因子κB受体激活剂配体的比例。暴露于CH的老年人全身骨密度增加，但特定区域没有增加。各组间脂肪百分比没有变化。