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Unloading-Induced Skeletal Interoception Alters Hypothalamic Signaling to Promote Bone Loss and Fat Metabolism.

ABSTRACT: Microgravity is the primary factor that affects human physiology in spaceflight, particularly bone loss and disturbances of the central nervous system. However, little is known about the cellular and molecular mechanisms of these effects. Here, it is reported that in mice hindlimb unloading stimulates expression of neuropeptide Y (NPY) and tyrosine hydroxylase (TH) in the hypothalamus, resulting in bone loss and altered fat metabolism. Enhanced expression of TH and NPY in the hypothalamus occurs downstream of a reduced prostaglandin E2 (PGE2)-mediated ascending interoceptive signaling of the skeletal interoception. Sympathetic antagonist propranolol or deletion of Adrb2 in osteocytes rescue bone loss in the unloading model. Moreover, depletion of TH⁺ sympathetic nerves or inhibition of norepinephrine release ameliorated bone resorption. Stereotactic inhibition of NPY expression in the hypothalamic neurons reduces the food intake with altered energy expenditure with a limited effect on bone, indicating hypothalamic neuroendocrine factor NPY in the facilitation of bone formation by sympathetic TH activity. These findings suggest that reduced PGE2-mediated interoceptive signaling in response to microgravity or unloading has impacts on the skeletal and central nervous systems that are reciprocally regulated.

SUBMITTER: Guo Q

PROVIDER: S-EPMC10724445 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Unloading-Induced Skeletal Interoception Alters Hypothalamic Signaling to Promote Bone Loss and Fat Metabolism.

Guo Qiaoyue Q Chen Ningrong N Patel Kalp K Wan Mei M Zheng Junying J Cao Xu X

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20231025 35

Microgravity is the primary factor that affects human physiology in spaceflight, particularly bone loss and disturbances of the central nervous system. However, little is known about the cellular and molecular mechanisms of these effects. Here, it is reported that in mice hindlimb unloading stimulates expression of neuropeptide Y (NPY) and tyrosine hydroxylase (TH) in the hypothalamus, resulting in bone loss and altered fat metabolism. Enhanced expression of TH and NPY in the hypothalamus occurs ...[more]

PMID: 37880864

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Project description:ObjectiveWith the deepening of magnetic biomedical effects and electromagnetic technology, some medical instruments based on static magnetic field (SMF) have been used in orthopedic-related diseases treatment. Studies have shown SMF could combat osteoporosis by regulating the differentiation of mesenchymal stem cells (MSCs), osteoblast and osteoclast. With the development of nanotechnology, iron oxide nanoparticles (IONPs) have been reported to regulate the process of bone anabolism. As for SMF combined with IONPs, studies indicated osteogenic differentiation of MSCs were promoted by the combination of SMF and IONPs. However, there are few reports on the effects of SMF combined with IONPs on osteoclast. Herein, the purpose of this study was to investigate the effects of high static magnetic field (HiSMF) combined with IONPs on unloading-induced bone loss in vivo and osteoclastic formation in vitro, and elucidated the potential molecular mechanisms.MethodsIn vivo, C57BL/6 J male mice were unloaded via tail suspension or housed normally. The hindlimb of mice were fixed and exposed to 1-2 T SMF for 1 h every day, 10 mg/kg of Ferumoxytol or saline were injected by tail vein once a week, last for 4 weeks. Bone microstructure, mechanical properties, and osteoclastogenesis were examined respectively. In vitro, the RAW264.7 cells were used to assess the effects of 1-2 T SMF combined with IONPs in osteoclastogenesis. The iron content was detected by atomic absorption spectrometry and Prussian blue staining. DCFH-DA and MitoSOX™ fluorescence staining were used to assess oxidative stress levels. NF-κB and MAPK signaling pathways were examined by western blot assay.ResultsIn vivo, the results showed 1-2 T SMF and IONPs prevented the damage to bone microstructure and improved the mechanical properties, diminished the number of osteoclasts in unloaded mice, 1-2 T SMF combined with IONPs was found more effective. The iron content in the liver and spleen was reduced by the combination of 1-2 T SMF and IONPs, enhancing iron levels in the femur. In vitro, osteoclast formation was inhibited by 1-2 T SMF and IONPs treatment, and 1-2 T SMF combined with IONPs had a more pronounced effect. Moreover, iron uptake of IONPs in osteoclast was reduced to 1-2 T SMF exposure. Oxidative stress levels were decreased in osteoclast differentiation under 1-2 T SMF combined with IONPs treatment. Molecularly, the expression of NF-κB and MAPK signaling pathways were inhibited under 1-2 T SMF combined with IONPs in osteoclastogenesis.ConclusionsSynthetically, our research illustrated 1-2 T SMF combined with IONPs prevented unloading-induced bone loss by regulating iron metabolism in osteoclastogenesis.Translational potential of this article: As a non-invasive alternative therapy, some medical instruments based on SMF have been used for orthopedic-related diseases treatment for their portability, cheapness and safety. Ferumoxytol (Feraheme™), the first FDA-approved IONP drug for the treatment of iron deficiency anemia, has been also adapted in translational research for osteoporosis. Based on the above-mentioned two points, we found the synergistic effects of SMF and Ferumoxytol for treatment of experimental osteoporosis. These results show translational potentials for clinical application.

Project description:BackgroundAn oligopeptide hepcidin is encoded by the human HAMP gene (Hamp in mice). Its deficiency can result in iron overload, while excess may lead to iron deficiency. Hepcidin knockout mice exhibited iron accumulation in multiple tissues, accompanied by degeneration of bone microarchitecture and reduced biomechanical properties. Astronauts who are exposed to weightlessness during prolonged spaceflight experience bone loss. After space missions, an interrelation exists between iron stores and bone mineral density (BMD). Bone loss in mice due to unloading is linked to iron excess and involves hepcidin. The potential role of hepcidin in unloading-induced bone loss remains unclear.MethodsOur study conducted relevant experiments using hepcidin knockout mice and their primary osteoblasts as the research subjects. We used the hindlimb unloading (HLU) model and the random positioning machine (RPM) system to simulate weightlessness in vivo and in vitro.ResultsHLU mice exhibited reduced hepcidin levels in the serum and liver. Hepcidin knockout further diminished BMD and bone mineral content (BMC) in the femurs of HLU mice. Similarly, the bone volume fraction (BV/TV) and connectivity density (Conn.Dn) followed this downward trend, whereas trabecular separation (Tb.Sp) showed an inverse pattern. Moreover, hepcidin knockout decreased the ultimate load and elastic modulus in the tibias of HLU mice. Hepcidin knockout decreased PINP levels in the serum, a commonly used marker for bone formation, alongside elevated iron levels in the serum, liver, and bone of HLU mice. We also found higher serum MDA and SOD levels in these mice. In vitro, experimental data indicated that hepcidin knockout suppresses the osteoblastic differentiation capacity under RPM conditions. Additionally, this condition upregulates SOST protein levels and downregulates LRP6 and β-catenin protein levels in osteoblasts.ConclusionHepcidin knockout exacerbates bone loss in HLU mice, most likely due to reduced osteoblastic activity.

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Unloading-Induced Skeletal Interoception Alters Hypothalamic Signaling to Promote Bone Loss and Fat Metabolism.

Publications

Unloading-Induced Skeletal Interoception Alters Hypothalamic Signaling to Promote Bone Loss and Fat Metabolism.

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