We previously demonstrated that Bmi1 deficiency leads to osteoporosis phenotype by inhibiting the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs), but it is unclear whether overexpression of Bmi1 in MSCs stimulates skeletal development and rescues Bmi1 deficiency‐induced osteoporosis. To answer this question, we constructed transgenic mice (Bmi1Tg) that overexpressed Bmi1 driven by the Prx1 gene and analyzed their skeletal phenotype differences with that of wild‐type littermates. We then hybridized Bmi1Tg to Bmi1−/− mice to generate Bmi1−/− mice overexpressing Bmi1 in MSCs and compared their skeletal phenotypes with those of Bmi1−/− and wild‐type mice using imaging, histopathological, immunohistochemical, histomorphometric, cellular, and molecular methods. Bmi1Tg mice exhibited enhanced bone growth and osteoblast formation, including the augmentation of bone size, cortical and trabecular volume, number of osteoblasts, alkaline phosphatase (ALP)‐positive and type I collagen‐positive areas, number of total colony forming unit fibroblasts (CFU‐f) and ALP+ CFU‐f, and osteogenic gene expression levels. Consistently, MSC overexpressing Bmi1 in the Bmi1−/− background not only largely reversed Bmi1 systemic deficiency‐induced skeletal growth retardation and osteoporosis, but also partially reversed Bmi1 deficiency‐induced systemic growth retardation and premature aging. To further explore the mechanism of action of MSCs overexpressing Bmi1 in antiosteoporosis and antiaging, we examined changes in oxidative stress and expression levels of p16 and p19. Our results showed that overexpression of Bmi1 in MSCs inhibited oxidative stress and downregulated p16 and p19. Taken together, the results of this study indicate that overexpression of Bmi1 in MSCs exerts antiaging and antiosteoporosis effects by inactivating p16/p19 signaling and inhibiting oxidative stress. stem cells 2019;37:1200–1211

Inflammatory bowel disease (IBD) affects 0.3% of the global population, yet the etiology remains poorly understood. Anti-inflammation therapy has shown great success, but only 60% of patients with IBD benefit from it, indicating that new targets are needed. Here, we report the discovery of an intrinsic counter regulatory mechanism in colitis pathogenesis that may be targeted for IBD treatment. In response to microbial invasion, resident Vimentin+ stromal cells, connective tissue cells genetically marked by Twist2, are activated during the propagation phase of the disease, but not during initiation and resolution phases, and become a primary source of prostaglandin E2 (PGE2). PGE2 induction requires a nuclear factor κB–independent, TLR4-p38MAPK-Cox2 pathway activation. Ablation of each of the pathway genes, but not Rela or Tgfb1, in Twist2 cells enhanced M1 macrophage polarization and granulocyte/T helper 1 (TH1)/TH17 infiltration and aggravated colitis development. PGE2 administration ameliorated colitis in mouse models with defective PGE2 production but not in animals with normal PGE2 induction. Analysis of clinical samples and public domain data revealed increased expression of Cox2, the rate-limiting enzyme of PGE2 biosynthesis, in inflamed tissues, and especially in colon Vimentin+Twist2+ stromal cells, in about 60% of patients with active Crohn’s disease or ulcerative colitis. Moreover, Cox2 protein expression was negatively correlated with disease severity, suggesting an involvement of stromal cells in IBD pathogenesis. Thus, the study uncovers an active immune pathway in colitic inflammation that may be targeted to treat patients with IBD with defects in PGE2 production.

NF‐κB is known to be implicated in skeletal development and related diseases. Previous studies have shown that RelA, a key subunit of NF‐κB, is involved in osteoblast and chondrocyte survival and differentiation. Yet, the physiological roles of RelA in mesenchymal stem cells (MSCs), which give rise to both chondrocytes and osteoblasts, are still poorly understood. Here, we generated Prrx1‐Cre;RelAf/f mice to delete RelA in Prrx1+ bone marrow MSCs and found that RelA deletion led to decreased MSC proliferation and altered differentiation, with increased osteogenic and chondrogenic differentiation but decreased adipogenic differentiation. Bone size and mass were not significantly changed in the mutant mice, although they developed moderate osteoarthritis‐like phenotypes. Thus, our studies reveal important but discordant functions of RelA in MSC proliferation and differentiation, and provide an explanation why MSC‐specific RelA knockout mice only develop minor skeletal phenotypes.

Bone homeostasis is a metabolic balance between the new bone formation by osteoblasts and old bone resorption by osteoclasts. Excessive osteoclastic bone resorption results in low bone mass, which is the major cause of bone diseases such as rheumatoid arthritis. Small GTPases Rac1 is a key regulator of osteoclast differentiation, but its exact mechanism is not fully understood. ELMO and DOCK proteins form complexes that function as guanine nucleotide exchange factors for Rac activation. Here, we report that ELMO1 plays an important role in differentiation and bone resorption of osteoclasts. Osteoclast precursors derived from bone marrow monocytes (BMMs) of Elmo1–/– mice display defective adhesion and migration during differentiation. The cells also have a reduced activation of Rac1, p38, JNK, and AKT in response to RANKL stimulation. Importantly, we show that bone erosion is alleviated in Elmo1–/– mice in a rheumatoid arthritis mouse model. Taken together, our results suggest that ELMO1, as a regulator of Rac1, regulates osteoclast differentiation and bone resorption both in vitro and in vivo.

Pharmacological activation of adaptive thermogenesis to increase energy expenditure is considered to be a novel strategy for obesity. Peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α), which serves as an inducible co-activator in energy expenditure, is highly expressed in brown adipose tissues (BAT). In this study, we found a PGC-1α transcriptional activator, natural compound rutaecarpine (Rut), which promoted brown adipocytes mitochondrial biogenesis and thermogenesis in vitro. Chronic Rut treatment reduced the body weight gain and mitigated insulin sensitivity through brown and beige adipocyte thermogenesis. Mechanistic study showed that Rut activated the energy metabolic pathway AMP-activated protein kinase (AMPK)/PGC-1α axis, and deficiency of AMPK abolished the beneficial metabolic phenotype of the Rut treatment in vitro and in vivo. In summary, a PGC-1α transcriptional activator Rut was found to activate brown and beige adipose thermogenesis to resist diet-induced obesity through AMPK pathway. Our findings serve as a further understanding of the natural compound in adipose tissue and provides a possible strategy to combat obesity and related metabolic disorders.