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The loss of bone fracture resistance in CKD results from both a loss of bone mass and decreased bone material properties, which together result from changes to the health and activities of bone cells. Determining changes to bone tissue metabolism with CKD may reveal insights important to monitoring and mitigating the decrease in bone fracture resistance with this disease. In this study, untargeted metabolomics was conducted on marrow-flushed cortical tibiae from female and male C57BL/6J mice fed either control or 0.2% w/w adenine diets for 3.5 or 7 wk. Liquid chromatography mass spectrometry assessed metabolites from tibia extracts. Group comparisons (adenine vs control, 7 wk vs 3.5 wk, female vs male) were conducted using principal components analysis and partial least squares discriminant analysis. Clusters of metabolites were also assessed using ensemble clustering with cluster optimization analysis. Volcano plots and variable importance in projections (VIP) scores identified metabolites that differed between groups, and pathway analyses were conducted using these features. Adenine-induced CKD produced few differences in cortical bone tissue metabolism, based on the comparison of pooled adenine vs control groups. However, pantothenate and Coenzyme-A biosynthesis, along with essential and nonessential amino acid pathways, registered notably high VIP scores for adenine vs control comparisons. There were many significant differences between 3.5- and 7-wk treatment groups (adenine and control). The pathways different between diet lengths for control mice reveal potential effects of skeletal aging. However, there were significant changes in the pentose phosphate pathway and cysteine metabolism between 3.5- and 7-wk adenine diets, indicating an effect of CKD severity. While sex differences in this study were modest, there was greater separation between female adenine vs control groups compared to male adenine vs control groups, indicating potential sex differences in the impacts of CKD on bone tissue metabolism. 

ObjectiveOsteoarthritis, the leading cause of disability worldwide, disproportionately affects women, yet sex remains an overlooked determinant. This disparity stems from sex‐specific differences in injury susceptibility—a major risk factor for disease. Using a non‐invasive injury model, we demonstrate that injury drives local and systemic metabolic alterations and that these responses differ by sex. MethodsMale and female mice were subjected to non‐invasive joint injury. Eight days after injury, serum, synovial fluid, and whole joints were collected for metabolomics. Additionally, whole joints were harvested for matrix‐assisted laser desorption ionization–mass spectrometry imaging (MALDI‐MSI) to capture the spatial distribution of molecular species and identify osteochondral regions perturbed by injury. ResultsComparative analyses among injured, contralateral, and naive mice revealed metabolomic alterations across sample types. Data indicate that injury influences metabolic profiles in whole joints, synovial fluid, and serum, with consistent dysregulation of amino acid, purine, and pyrimidine metabolism, indicating a systemic effect of localized injury. Additionally, sex‐dependent differences emerged across tissues, highlighting sexually dimorphic pathways following injury. MALDI‐MSI generated 2D ion images of bone, the joint interface, and bone marrow, identifying region‐specific metabolic changes following injury. ConclusionJoint injury induces coordinated metabolic responses locally and systemically that extend beyond the injured joint and are influenced by sex. Integrating metabolomic and spatial analyses reveals how injury modulates joint pathophysiology across tissues and reveals sex‐specific patterns relevant to post‐traumatic osteoarthritis (PTOA) risk. These findings improve preclinical PTOA models and deepen our understanding of the complex role of injury and sex in osteoarthritis pathogenesis, laying the foundation for targeted therapeutic strategies.image 

ABSTRACT The gut microbiome impacts bone mass, which implies a disruption to bone homeostasis. However, it is not yet clear how the gut microbiome affects the regulation of bone mass and bone quality. We hypothesized that germ‐free (GF) mice have increased bone mass and decreased bone toughness compared with conventionally housed mice. We tested this hypothesis using adult (20‐ to 21‐week‐old) C57BL/6J GF and conventionally raised female and male mice ( n  = 6–10/group). Trabecular microarchitecture and cortical geometry were measured from micro–CT of the femur distal metaphysis and cortical midshaft. Whole‐femur strength and estimated material properties were measured using three‐point bending and notched fracture toughness. Bone matrix properties were measured for the cortical femur by quantitative back‐scattered electron imaging and nanoindentation, and, for the humerus, by Raman spectroscopy and fluorescent advanced glycation end product (fAGE) assay. Shifts in cortical tissue metabolism were measured from the contralateral humerus. GF mice had reduced bone resorption, increased trabecular bone microarchitecture, increased tissue strength and decreased whole‐bone strength that was not explained by differences in bone size, increased tissue mineralization and fAGEs, and altered collagen structure that did not decrease fracture toughness. We observed several sex differences in GF mice, most notably for bone tissue metabolism. Male GF mice had a greater signature of amino acid metabolism, and female GF mice had a greater signature of lipid metabolism, exceeding the metabolic sex differences of the conventional mice. Together, these data demonstrate that the GF state in C57BL/6J mice alters bone mass and matrix properties but does not decrease bone fracture resistance. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).