Gut microbial alterations in arginine metabolism determine bone mechanical adaptation.

Although mechanical loading is essential for maintaining bone health and combating osteoporosis, its practical application is limited to a large extent by the high variability in bone mechanoresponsiveness. Here, we found that gut microbial depletion promoted a significant reduction in skeletal adaptation to mechanical loading. Among experimental mice, we observed differences between those with high and low responses to exercise with respect to the gut microbial composition, in which the differential abundance of Lachnospiraceae contributed to the differences in bone mechanoresponsiveness. Microbial production of L-citrulline and its conversion into L-arginine were identified as key regulators of bone mechanoadaptation, and administration of these metabolites enhanced bone mechanoresponsiveness in normal, aged, and ovariectomized mice. Mechanistically, L-arginine-mediated enhancement of bone mechanoadaptation was primarily attributable to the activation of a nitric-oxide-calcium positive feedback loop in osteocytes. This study identifies a promising anti-osteoporotic strategy for maximizing mechanical loading-induced skeletal benefits via the microbiota-metabolite axis.

Stress reduction through cortical bone thickening improves bone mechanical behavior in adult female Beclin-1+/- mice.

Fragility fractures, which are more prevalent in women, may be significantly influenced by autophagy due to altered bone turnover. As an essential mediator of autophagy, Beclin-1 modulates bone homeostasis by regulating osteoclast and chondrocyte differentiation, however, the alteration in the local bone mechanical environment in female Beclin-1+/- mice remains unclear. In this study, our aim is to investigate the biomechanical behavior of femurs from seven-month-old female wild-type (WT) and Beclin-1+/- mice under peak physiological load, using finite element analysis on micro-CT images. Micro-CT imaging analyses revealed femoral cortical thickening in Beclin-1+/- female mice compared to WT. Three-point bending test demonstrated a 63.94% increase in whole-bone strength and a 61.18% increase in stiffness for female Beclin-1+/- murine femurs, indicating improved biomechanical integrity. After conducting finite element analysis, Beclin-1+/- mice exhibited a 26.99% reduction in von Mises stress and a 31.62% reduction in maximum principal strain in the femoral midshaft, as well as a 36.64% decrease of von Mises stress in the distal femurs, compared to WT mice. Subsequently, the strength-safety factor was determined using an empirical formula, revealing that Beclin-1+/- mice exhibited significantly higher minimum safety factors in both the midshaft and distal regions compared to WT mice. In summary, considering the increased response of bone adaptation to mechanical loading in female Beclin-1+/- mice, our findings indicate that increasing cortical bone thickness significantly improves bone biomechanical behavior by effectively reducing stress and strain within the femoral shaft.

ASC Regulates Subcutaneous Adipose Tissue Lipogenesis and Lipolysis via p53/AMPKα Axis.

Obesity has become an extensive threat to human health due to associated chronic inflammation and metabolic diseases. Apoptosis-associated speck-like protein (ASC) is a critical link between inflammasome and apoptosis-inducing proteins. In this study, we aimed to clarify the role of ASC in lipid metabolism. With high-fat diet (HFD) and knockout leptin gene mice (ob/ob), we found that ASC expression in subcutaneous adipose tissue (SAT) correlated with obesity. It could also positively regulate the reprogramming of cellular energy metabolism. Stromal vascular fractions (SVF) cells derived from the SAT of Asc-/- mice or SVF from wild-type (WT) mice transfected with ASC siRNA were used to further investigate the underlying molecular mechanisms. We found ASC deficiency could lead to lipogenesis and inhibit lipolysis in SAT, aggravating lipid accumulation and impairing metabolic balance. In addition, our results showed that p53 and AMPKα expression were inhibited in SAT when ASC level was low. p53 and AMP-activated protein kinase α (AMPKα) were then assessed to elucidate whether they were downstream of ASC in regulating lipid metabolism. Our results revealed that ASC deficiency could promote lipid accumulation by increasing lipogenesis and decreasing lipolysis through p53/AMPKα axis. Regulation of ASC on lipid metabolism might be a novel therapeutic target for obesity.

Chemerin located in bone marrow promotes osteogenic differentiation and bone formation via Akt/Gsk3ß/ß-catenin axis in mice.

Chemerin, a secreted protein mainly produced by adipocytes and hepatocytes, plays a variety of roles in endocrine or paracrine signaling. As reported in human epidemiology, chemerin was correlated with osteoporosis. And the previous in vitro study found that chemerin knockdown promoted osteogenesis and inhibited adipogenesis. However, the function of chemerin in bone metabolism and the underlying mechanism remains unclear. In this study, we uncovered the in vivo function of chemerin in bone homeostasis. We discovered that in obese mice, chemerin was increased in serum, while decreased in the bone marrow; and the chemerin expression in bone tissue was positively correlated with osteogenic genes. To further investigate the function of chemerin in bone metabolism, we generated chemerin deficiency and overexpression mice. We found bone mass and osteogenesis were decreased in chemerin deficiency mice, while were increased in chemerin overexpression mice. Furthermore, we observed that the chemerin expression increased during osteogenic differentiation of MSCs. Besides, we verified that chemerin promoted osteogenic differentiation in C3H10T1/2 cells and BMSCs through Akt/Gsk3ß/ß-catenin axis. Treatment with Akt inhibitor (MK2206) abolished the promoting effect of chemerin on osteogenic differentiation and active ß-catenin. Together, our results suggest chemerin in bone marrow, not in serum, promotes osteogenic differentiation and bone formation via Akt/Gsk3ß/ß-catenin axis. Chemerin may serve as a therapeutic strategy for osteoporosis.

A Potential Participant in Type 2 Diabetes Bone Fragility: TIMP-1 at Sites of Osteocyte Lacunar-Canalicular System.

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of bone fracture, but the bone mineral density (BMD) is typically normal or higher in such patients. Because the fracture risk is independent of reduced BMD, bone fragility in T2DM may be partially due to poor bone quality. The mechanisms triggering bone quality abnormalities in T2DM are complex, and include the accumulation of advanced glycation end-products, the increased inflammation, and low bone turnover. Matrix metalloproteinases (MMPs) in bone can hydrolyze the bone matrix. Tissue inhibitors of MMPs (TIMPs) can inhibit the activity of MMPs. Both MMPs and TIMPs participate in mediating bone quality. Among all types of TIMPs, TIMP-1 is mostly reportedly increased in the serum of T2DM patients. Because osteocytes can express TIMP-1, and osteocyte pericellular matrix influences bone quality partially regulated by perilacunar/canalicular remodeling, we hypothesized that TIMP-1 at sites of osteocyte lacunar-canalicular system is involved in T2DM bone fragility.

Multifunctional Islet Transplantation Hydrogel Encapsulating A20 High-Expressing Islets.

Islet transplantation is regarded as the most promising treatment for type 1 diabetes (T1D). However, the function of grafted islet could be damaged on account of transplant rejection and/or hypoxia several years later after transplantation. We proposed a hypothetical functionalized hydrogel model, which encapsulates sufficient A20 high-expressing islets and supporting cells, and performs as a drug release system releasing immunosuppressants and growth factors, to improve the outcome of pancreatic islet transplantation. Once injected in vivo, the hydrogel can gel and offer a robust mechanical structure for the A20 high-expressing islets and supporting cells. The natural biomaterials (eg, heparin) added into the hydrogel provide adhesive sites for islets to promote islets' survival. Furthermore, the hydrogel encapsulates various supporting cells, which can facilitate the vascularization and/or prevent the immune system attacking the islet graft. Based on the previous studies that generally applied one or two combined strategies to protect the function of islet graft, we designed this hypothetical multifunctional encapsulation hydrogel model with various functions. We hypothesized that the islet graft could survive and maintain its function for a longer time in vivo compared with naked islets. This hypothetical model has a limitation in terms of clinical application. Future development work will focus on verifying the function and safety of this hypothetical islet transplantation hydrogel model in vitro and in vivo.

Identification of Potential Metabolite Markers for Middle-Aged Patients with Post-Stroke Depression Using Urine Metabolomics.

BACKGROUND: Post-stroke depression (PSD) is one of the most common complications in stroke survivors. But, there are still no objective methods to diagnose PSD. This study aims to identify potential biomarkers for diagnosing PSD in middle-aged stroke survivors. METHODS: Middle-aged subjects aged 30 to 59 years (92 PSD patients and 89 stroke survivors without depression) were included in this study. Urinary metabolites were detected by gas chromatography-mass spectrometry (GC-MS). Differential urinary metabolites and potential biomarkers were screened by applying statistical analysis. RESULTS: The different urinary metabolic phenotypes between PSD patients and stroke survivors without depression were identified. A total of 12 differential urinary metabolites were accurately identified by using orthogonal partial least-squares-discriminant analysis. After analyzing those 12 differential urinary metabolites by step-wise logistic regression analysis, only seven metabolites (palmitic acid, hydroxylamine, myristic acid, glyceric acid, lactic acid, tyrosine and azelaic acid) were finally selected as potential biomarkers for diagnosing PSD in middle-aged stroke survivors. A panel consisting of these potential biomarkers could effectively diagnose middle-aged PSD patients. CONCLUSION: Urinary metabolic profiles were different between middle-aged PSD patients and stroke survivors without depression. Our results would be helpful in future for developing an objective method to diagnose PSD in middle-aged stroke survivors.