Boregowda Siddaraju V, Ghoshal Sarbani, Booker Cori N, Krishnappa Veena, Chakraborty Anutosh, Phinney Donald G
Department of Molecular Medicine, The Scripps Research Institute-Scripps Florida, Jupiter, Florida, USA.
Stem Cells. 2017 Aug;35(8):1973-1983. doi: 10.1002/stem.2645. Epub 2017 Jun 15.
Mesenchymal stem/stromal cells (MSCs) are the predominant source of bone and adipose tissue in adult bone marrow and play a critical role in skeletal homeostasis. Age-induced changes in bone marrow favor adipogenesis over osteogenesis leading to skeletal involution and increased marrow adiposity so pathways that prevent MSC aging are potential therapeutic targets for treating age-related bone diseases. Here, we show that inositol hexakisphosphate kinase 1 (Ip6k1) deletion in mice increases MSC yields from marrow and enhances cell growth and survival ex vivo. In response to the appropriate stimuli, Ip6k1 versus Ip6k1 MSCs also exhibit enhanced osteogenesis and hematopoiesis-supporting activity and reduced adipogenic differentiation. Mechanistic-based studies revealed that Ip6k1 MSCs express higher MDM2 and lower p53 protein levels resulting in lower intrinsic mitochondrial reactive oxygen species (ROS) levels as compared to Ip6k1 MSCs, but both populations upregulate mitochondrial ROS to similar extents in response to oxygen-induced stress. Finally, we show that mice fed a high fat diet exhibit reduced trabecular bone volume, and that pharmacological inhibition of IP6K1 using a pan-IP6K inhibitor largely reversed this phenotype while increasing MSC yields from bone marrow. Together, these findings reveal an important role for IP6K1 in regulating MSC fitness and differentiation fate. Unlike therapeutic interventions that target peroxisome proliferator-activated receptor gamma and leptin receptor activity, which yield detrimental side effects including increased fracture risk and altered feeding behavior, respectively, inhibition of IP6K1 maintains insulin sensitivity and prevents obesity while preserving bone integrity. Therefore, IP6K1 inhibitors may represent more effective insulin sensitizers due to their bone sparing properties. Stem Cells 2017;35:1973-1983.
间充质干/基质细胞（MSCs）是成年骨髓中骨和脂肪组织的主要来源，在骨骼稳态中起关键作用。年龄诱导的骨髓变化有利于脂肪生成而非骨生成，导致骨骼退化和骨髓脂肪增多，因此，阻止间充质干细胞衰老的途径是治疗与年龄相关的骨疾病的潜在治疗靶点。在此，我们表明，小鼠中肌醇六磷酸激酶1（Ip6k1）缺失可提高骨髓中间充质干细胞的产量，并增强其体外细胞生长和存活能力。在适当刺激下，Ip6k1基因敲除的间充质干细胞与野生型间充质干细胞相比，还表现出增强的成骨能力和造血支持活性，以及减少的脂肪生成分化。基于机制的研究表明，与野生型间充质干细胞相比，Ip6k1基因敲除的间充质干细胞表达更高水平的MDM2和更低水平的p53蛋白，导致其内在线粒体活性氧（ROS）水平更低，但在氧诱导应激反应中，这两种细胞群体上调线粒体ROS的程度相似。最后，我们表明，高脂饮食喂养的小鼠小梁骨体积减少，使用泛IP6K抑制剂对IP6K1进行药理学抑制在很大程度上逆转了这种表型，同时增加了骨髓中间充质干细胞的产量。总之，这些发现揭示了IP6K1在调节间充质干细胞适应性和分化命运中的重要作用。与分别针对过氧化物酶体增殖物激活受体γ和瘦素受体活性的治疗干预措施不同，这些措施会产生有害的副作用，包括骨折风险增加和进食行为改变，抑制IP6K1可维持胰岛素敏感性并预防肥胖，同时保持骨骼完整性。因此，由于其保护骨骼的特性，IP6K1抑制剂可能代表更有效的胰岛素增敏剂。《干细胞》2017年；35:1973 - 1983。
