IP6K1 Reduces Mesenchymal Stem/Stromal Cell Fitness and Potentiates High Fat Diet-Induced Skeletal Involution

Abstract

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

Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases

“…Conversely, they show reduced adipogenesis, which further explains diminished adipose mass in these animals. Ip6k1-KO BMMSCs display reduced ROS level [41]. Accordingly, long-term TNP treatment increases yield and colony-formation capacity of MSCs in high fat diet induced obese mice [41,42].…”

“…Table 1. Summary of the metabolic parameters of Ip6k1-KO [22,30,41], AdKO [29], Ip6k3-KO [34] and TNP-treated WT [42] mouse models in ambient temperature conditions. Symbols ↑, ↓ and = denote increase, decrease and no change, respectively.…”

“…In 2014, 54 million US adults were affected by osteoporosis. Bone marrow derived mesenchymal stem/stromal cells (BMMSCs) are the predominant source of osteocytes and adipocytes in the bone marrow [41,178]. Age or obesity induced oxidative and other changes in the bone marrow favors adipogenesis over osteogenesis, leading to skeletal involution and marrow adiposity [179][180][181].…”

“…Age or obesity induced oxidative and other changes in the bone marrow favors adipogenesis over osteogenesis, leading to skeletal involution and marrow adiposity [179][180][181]. Thus, pathways that induce osteogenesis and/or reduce adipogenesis of BMMSC are potential therapeutic targets to treat obesity or age related bone diseases [41]. Ip6k1, the major Ip6k-isotype in BMMSC regulates stem cell fitness.…”

“…As Ip6k1 is the major murine isotype, Ip6k1-KO mice were characterized first, followed by Ip6k2 and Ip6k3 knockouts ( [12,25], and references therein), whereas PPIP5Ks are currently being studied [37][38][39]. Genetic deletion of Ip6k1 or Ip6k3 or pharmacologic disruption of IP6Ks protects mice from metabolic diseases including obesity, type-2 diabetes (T2D), non-alcoholic fatty liver (NAFL), osteoporosis, myocardial infarction, ischemia reperfusion injury and aging [22,29,34,[40][41][42][43][44][45]. These discoveries drew the attention of pharmaceutical companies.…”