Mitochondrial complex I (CI) deficiency is associated with multiple neurological and metabolic disorders. However, its effect on innate immunity and bone remodeling is unclear. Using deletion of the ...essential CI subunit Ndufs4 as a model for mitochondrial dysfunction, we report that mitochondria suppress macrophage activation and inflammation while promoting osteoclast differentiation and bone resorption via both cell-autonomous and systemic regulation. Global Ndufs4 deletion causes systemic inflammation and osteopetrosis. Hematopoietic Ndufs4 deletion causes an intrinsic lineage shift from osteoclast to macrophage. Liver Ndufs4 deletion causes a metabolic shift from fatty acid oxidation to glycolysis, accumulating fatty acids and lactate (FA/LAC) in the circulation. FA/LAC further activates Ndufs4−/− macrophages via reactive oxygen species induction and diminishes osteoclast lineage commitment in Ndufs4−/− progenitors; both inflammation and osteopetrosis in Ndufs4−/− mice are attenuated by TLR4/2 deletion. Together, these findings reveal mitochondrial CI as a critical rheostat of innate immunity and skeletal homeostasis.
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•Mitochondrial dysfunction triggers macrophage activation and systemic inflammation•Mitochondrial dysfunction impairs osteoclast differentiation and bone resorption•Mitochondria play a cell-intrinsic role in osteoclast-macrophage lineage allocation•Mitochondria alter metabolism to modulate osteoclast-macrophage function
Jin et al. reveal that mitochondrial complex I acts as a critical rheostat of innate immunity and bone remodeling by suppressing macrophage activation and inflammation while promoting osteoclast differentiation and bone resorption via cell-autonomous and systemic regulations.
Osteoclasts are bone-resorbing cells essential for skeletal remodeling and regeneration. However, excessive osteoclasts often contribute to prevalent bone degenerative diseases such as osteoporosis, ...arthritis, and cancer bone metastasis. Osteoclast dysregulation is also associated with rare disorders such as osteopetrosis, pycnodysostosis, Paget's disease, and Gorham-Stout syndrome. The nuclear receptor (NR) family of transcription factors functions as metabolic sensors that control a variety of physiological processes including skeletal homeostasis and serves as attractive therapeutic targets for many diseases. In this review, we highlight recent findings on the new players and the new mechanisms for how NRs regulate osteoclast differentiation and bone resorption. An enhanced understanding of NR functions in osteoclastogenesis will facilitate the development of not only novel osteoprotective medicine but also prudent strategies to minimize the adverse skeletal effects of certain NR-targeting drugs for a better treatment of cancer and metabolic diseases.
The immunopathogenic process from hepatitis B virus (HBV) infection to liver fibrosis is incompletely understood because it lacks an animal model. In this study we observed the development of liver ...fibrosis in HBV transgenic (HBV‐tg) mice and found the roles of natural killer T (NKT) cells in HBV‐related liver fibrosis. We found liver fibrosis spontaneously developed in HBV‐tg mice with the elevated transcription of col1a1, matrix metalloproteinase (MMP)2, and tissue inhibitor of metalloproteinase (TIMP)1. Mice were then injected with repetitive hepatotoxin carbon tetrachloride (CCl4) to induce prominent liver fibrosis. After chronic CCl4 treatment, the serum alanine aminotransferase (ALT) was higher, the liver regenerative nodules became more and bigger, and the fibrosis area was remarkably increased in HBV‐tg mice than in C57BL/6 mice. Moreover, the increase in col1a1 and MMP2 transcription was greater, with a sustaining high level of TIMP1 and a greater activation of hepatic stellate cells (HSCs) in the livers of CCl4‐treated HBV‐tg mice. Our data also showed that there were more liver mononuclear cells (MNCs) in HBV‐tg mice after CCl4 injection, and Rag1−/− mice adoptive transferred lymphocytes from HBV‐tg mice displayed increased collagen deposition. Further study demonstrated the number of liver NKT cells increased after CCl4 treatment and NKT cells were overactivated in HBV‐tg mice in the long term. It was further confirmed that NKT cells were critical for HSCs activation by depletion of NKT cells of HBV‐tg mice and adoptive transfer of purified NKT cells from HBV‐tg mice into recipient Rag1−/− mice. The inflammatory cytokines IL‐4 and IL‐13 produced by NKT cells played a pivotal role in HSCs activation in an in vitro coculture experiment. Conclusion: These data suggest that NKT cells from HBV‐tg mice induce the HSC activation in liver fibrogenesis. (HEPATOLOGY 2011;.)
Individuals with type 1 diabetes (T1D) have an increased risk of osteoporosis and fracture. In this issue of Cell Chemical Biology, Ji et al.1 show that impaired glucose metabolism in the ...bone-forming osteoblast drives diabetic osteoporosis in Akita mice, a mouse model of T1D.
Individuals with type 1 diabetes (T1D) have an increased risk of osteoporosis and fracture. In this issue of Cell Chemical Biology, Ji et al. show that impaired glucose metabolism in the bone-forming osteoblast drives diabetic osteoporosis in Akita mice, a mouse model of T1D.
Orexin neuropeptides promote arousal, appetite, reward, and energy expenditure. However, whether orexin affects bone mass accrual is unknown. Here, we show that orexin functions centrally through ...orexin receptor 2 (OX2R) in the brain to enhance bone formation. OX2R null mice exhibit low bone mass owing to elevated circulating leptin, whereas central administration of an OX2R-selective agonist augments bone mass. Conversely, orexin also functions peripherally through orexin receptor 1 (OX1R) in the bone to suppress bone formation. OX1R null mice exhibit high bone mass owing to a differentiation shift from marrow adipocyte to osteoblast that results from higher osseous ghrelin expression. The central action is dominant because bone mass is reduced in orexin null and OX1R2R double null mice but enhanced in orexin-overexpressing transgenic mice. These findings reveal orexin as a critical rheostat of skeletal homeostasis that exerts a yin-yang dual regulation and highlight orexin as a therapeutic target for osteoporosis.
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•Orexin centrally enhances bone formation via OX2R by reducing circulating leptin•Orexin peripherally inhibits bone formation via OX1R by reducing osseous ghrelin•OX1R activation suppresses osteoblast differentiation from mesenchymal stem cell•Orexin augments bone mass because central action is dominant over peripheral action
Wei et al. show that the neuropeptide orexin affects bone mass through a yin-yang dual regulation of orexin receptor 2 in the brain, which enhances bone formation, and orexin receptor 1 in the bone, which suppresses bone formation.
SLC7A7 deficiency, or lysinuric protein intolerance (LPI), causes loss of function of the y+LAT1 transporter critical for efflux of arginine, lysine and ornithine in certain cells. LPI is ...characterized by urea cycle dysfunction, renal disease, immune dysregulation, growth failure, delayed bone age, and osteoporosis. We previously reported that Slc7a7 knockout mice (C57BL/6 x 129/SvEv F2) recapitulate LPI phenotypes, including growth failure. Our main objective was to characterize the skeletal phenotype in these mice. Compared to wild type littermates, juvenile Slc7a7 knockout mice demonstrated 70% lower body weights, 87% lower plasma IGF-1 concentrations, and delayed skeletal development. Because poor survival prevents evaluation of mature knockout mice, we generated a conditional Slc7a7 deletion in mature osteoblasts or mesenchymal cells of the osteo-chondroprogenitor lineage, butno differences in bone architecture were observed. Overall, global Slc7a7 deficiency caused growth failure with low plasma IGF-1 concentrations and delayed skeletal development, but Slc7a7 deficiency in the osteoblastic lineage was not a major contributor to these phenotypes. Future studies utilizing additional tissue-specific Slc7a7 knockout models may help dissect cell autonomous and non-cell autonomous mechanisms underlying phenotypes in LPI.
Inhaled nitric oxide (NO) therapy has been reported to improve lung growth in premature newborns. However, the underlying mechanisms by which NO regulates lung development remain largely unclear. NO ...is enzymatically produced by three isoforms of nitric oxide synthase (NOS) enzymes. NOS knockout mice are useful tools to investigate NO function in the lung. Each single NOS knockout mouse does not show obvious lung alveolar phenotype, likely due to compensatory mechanisms. While mice lacking all three NOS isoforms display impaired lung alveolarization, implicating NO plays a pivotal role in lung alveolarization. Argininosuccinate lyase (ASL) is the only mammalian enzyme capable of synthesizing L-arginine, the sole precursor for NOS-dependent NO synthesis. ASL is also required for channeling extracellular L-arginine into a NO-synthetic complex. Thus, ASL deficiency (ASLD) is a non-redundant model for cell-autonomous, NOS-dependent NO deficiency. Here, we assessed lung alveolarization in ASL-deficient mice. Hypomorphic deletion of Asl (AslNeo/Neo) results in decreased lung alveolarization, accompanied with reduced level of S-nitrosylation in the lung. Genetic ablation of one copy of Caveolin-1, which is a negative regulator of NO production, restores total S-nitrosylation as well as lung alveolarization in AslNeo/Neo mice. Importantly, NO supplementation could partially rescue lung alveolarization in AslNeo/Neo mice. Furthermore, endothelial-specific knockout mice (VE-Cadherin Cre; Aslflox/flox) exhibit impaired lung alveolarization at 12 weeks old, supporting an essential role of endothelial-derived NO in the enhancement of lung alveolarization. Thus, we propose that ASLD is a model to study NO-mediated lung alveolarization.
Nitric oxide (NO) is a critical signaling molecule that has been implicated in the pathogenesis of neurocognitive diseases. Both excessive and insufficient NO production have been linked to ...pathology. Previously, we have shown that argininosuccinate lyase deficiency (ASLD) is a novel model system to investigate cell-autonomous, nitric oxide synthase-dependent NO deficiency. Humans with ASLD are at increased risk for developing hyperammonemia due to a block in ureagenesis. However, natural history studies have shown that individuals with ASLD have multisystem disease including neurocognitive deficits that can be independent of ammonia. Here, using ASLD as a model of NO deficiency, we investigated the effects of NO on brain endothelial cells in vitro and the blood-brain barrier (BBB) in vivo. Knockdown of ASL in human brain microvascular endothelial cells (HBMECs) led to decreased transendothelial electrical resistance, indicative of increased cell permeability. Mechanistically, treatment with an NO donor or inhibition of Claudin-1 improved barrier integrity in ASL-deficient HBMECs. Furthermore, in vivo assessment of a hypomorphic mouse model of ASLD showed increased BBB leakage, which was partially rescued by NO supplementation. Our results suggest that ASL-mediated NO synthesis is required for proper maintenance of brain microvascular endothelial cell functions as well as BBB integrity.
Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer. MicroRNAs play important roles in physiology and disease, and present tremendous therapeutic ...potential. Nonetheless, how microRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is downregulated during osteoclast differentiation. Osteoclastic miR-34a-overexpressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify transforming growth factor-β-induced factor 2 (Tgif2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers.
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