Introduction: Osteoporosis weakens the skeleton by lowering bone mass and damaging bone microarchitecture. A growing body of evidence points to disruptions in osteoimmune homeostasis as a key driver of this disease. In particular, apoptosis of bone cells and immune cells appears to be a critical contributing mechanism. Within the bone marrow, CD8 ⁺ T cells display a surprising functional duality: whether they protect bone or promote its loss depends heavily on local signals. Under healthy conditions or after mechanical loading, activated CD8 ⁺ T cells help maintain bone mass. They do so mainly by secreting interferon‑γ (IFN‑γ), which blocks osteoclast formation through interference with NF‑κB and MAPK signaling. However, this protective role is not fixed. Pathological cues such as estrogen deficiency can flip CD8 ⁺ T cells into a bone‑destroying phenotype. For example, when estrogen drops, muscle‑derived IL‑33 decreases. That drop prompts bone marrow CD8 ⁺ T cells to release large amounts of CCL5. CCL5 then binds to CCR3 on osteoclast precursors and activates the ERK pathway, thereby accelerating bone loss in postmenopausal osteoporosis. Aging and chronic inflammation add another layer of complexity. They drive the accumulation of senescent CD28 ^- CD8 ⁺ T cells. These aged cells no longer produce enough IFN‑γ to protect bone; instead, they adopt a senescence‑associated secretory phenotype (SASP) that suppresses osteoblast differentiation and reduces mesenchymal stromal cell viability. Moreover, apoptosis of osteoblasts and osteocytes—triggered by TNF‑α, IFN‑γ, or glucocorticoids—worsens bone loss. New findings suggest that CD8 ⁺ T cells may fuel this apoptotic process through Fas/FasL interactions and the granzyme/perforin pathway. This review brings together these context‑dependent mechanisms. We place special emphasis on how hormonal shifts, metabolic changes, and inflammatory mediators converge to decide whether CD8 ⁺ T cells support skeletal integrity or drive bone resorption. Methods: We performed a narrative review of recent studies on CD8 ⁺ T cells in osteoporosis. We searched PubMed and Web of Science using keywords such as “osteoporosis”, “osteoimmunology”, “CD8 ⁺ T cells”, “IFN‑γ”, “CCL5”, “cellular senescence”, “SASP”, “Fas/FasL”, and “granzyme”. From the retrieved articles, we selected original research (including in vitro co‑culture systems, animal models, and clinical samples) and relevant reviews. We then extracted and integrated key mechanistic evidence regarding the dual functionality of CD8 ⁺ T cells and its regulatory pathways. Results: CD8 ⁺ T cells have two opposing functions. Under healthy conditions or mechanical loading, activated CD8 ⁺ T cells secrete IFN‑γ, which inhibits osteoclast formation by interfering with NF‑κB and MAPK signaling, thus maintaining bone mass. In contrast, when estrogen is deficient, reduced muscle‑derived IL‑33 causes bone marrow CD8 ⁺ T cells to release large amounts of CCL5. CCL5 binds to CCR3 on osteoclast precursors and activates the ERK pathway, accelerating bone loss. Aging and chronic inflammation shift the balance. Aging and chronic inflammation lead to the accumulation of senescent CD28 ^- CD8 ⁺ T cells. These cells no longer produce sufficient protective IFN‑γ. Instead, they exhibit a senescence‑associated secretory phenotype (SASP) that suppresses osteoblast differentiation and reduces mesenchymal stromal cell viability. CD8 ⁺ T cells may promote bone cell apoptosis through multiple pathways. TNF‑α, IFN‑γ, or glucocorticoids can trigger apoptosis of osteoblasts and osteocytes. Newer evidence suggests that CD8 ⁺ T cells amplify this process via Fas/FasL interactions and the granzyme/perforin pathway. Two newly identified CD8 ⁺ T cell‑derived molecules deserve attention. Granzyme K protects against bone loss, whereas CCL5 promotes bone loss. These two molecules offer fresh opportunities for biomarkers and therapies. Discussion: Our synthesis shows that CD8 ⁺ T cells act as a double‑edged sword in osteoporosis: their functional switch depends on the integration of hormonal, metabolic, and inflammatory signals. Under normal conditions or after mechanical loading, the anti‑osteoclastogenic effect of IFN‑γ dominates. But when estrogen levels fall, the IL‑33/CCL5/CCR3/ERK axis becomes activated, turning CD8 ⁺ T cells toward a bone‑resorbing phenotype. During aging, the buildup of CD28⁻ CD8 ⁺ T cells and their SASP further weakens bone formation and worsens bone cell death through apoptotic pathways. These observations point to a more precise therapeutic strategy. Instead of broadly modulating T cells, one could specifically target pathogenic pathways—for example, by interfering with the IL 33/ST2/CCL5 cascade or by clearing immune senescent CD28⁻ subsets. Such approaches might help restore osteoimmune balance. Two recently discovered CD8 ⁺ T cell derived molecules, granzyme K and CCL5, are particularly interesting because they respectively protect against and promote bone loss. They could serve as novel biomarkers or even therapeutic targets. Future studies should examine the cell type specific regulation of these pathways in vivo and test the safety and efficacy of targeted interventions.

The gut microbiota regulates bone metabolism via a complex gut-bone axis involving short-chain fatty acids (SCFAs), immune modulation, and neuroendocrine signals. However, the precise mechanisms remain unclear, and microbiota-targeted interventions (probiotics, prebiotics, fecal microbiota transplantation) are not yet optimized for clinical use. This review systematically synthesizes the immune-metabolic-neural interaction network within the gut-bone axis, highlighting non-linear crosstalk among SCFAs, bile acids, tryptophan derivatives, immune cells (macrophages, Treg/Th17), and vagus nerve signaling. We critically assess translational hurdles, including heterogeneous study designs, confounding factors, and lack of causal evidence. Based on this network perspective, we propose a framework for future research that prioritizes multi-omics approaches, stratified interventions, and rigorous trials. This synthesis advances understanding of how gut dysbiosis drives bone disorders and paves the way for precision skeletal medicine. This review identifies microbial markers for risk stratification of bone metabolic disorders and discusses SCFA-based strategies and fecal microbiota transplantation (FMT) in conditions including osteoporosis, impaired fracture healing, rheumatoid arthritis, and glucocorticoid-associated osteonecrosis. It provides testable hypotheses for large-scale randomized controlled trials (RCTs), directly supporting translation of microbiome research into clinical practice for bone disorders.

Osteoporosis is a metabolic bone disease that seriously jeopardizes the health of middle‐aged and elderly people. Mesenchymal stem cell‐based transplantation for osteoporosis is a promising new therapeutic strategy. Induced mesenchymal stem cells (iMSCs) are a new option for stem cell transplantation therapy. Acquired mouse skin fibroblasts were transduced and reprogrammed into induced pluripotent cells and further induced to differentiate into iMSCs. The iMSCs were tested for pluripotency markers, trilineage differentiation ability, cell surface molecular marker tests, and gene expression patterns. The iMSCs were injected into the tail vein of mice by tail vein injection, and the distribution of cells in various organs was observed. The effect of iMSCs on the bone mass of mice was detected after injection into the mouse osteoporosis model. The effects of iMSCs infusion on metabolites in femoral tissue and peripheral blood plasma were detected based on LC–MS untargeted metabolomics. iMSCs have similar morphology, immunophenotype, in vitro differentiation potential, and gene expression patterns as mesenchymal stem cells. The iMSCs were heavily distributed in the lungs after infusion and gradually decreased over time. The iMSCs in the femoral bone marrow cavity gradually increased with time. iMSCs infusion significantly avoided bone loss due to oophorectomy. The results of untargeted metabolomics suggest that amino acid and lipid metabolic pathways are key factors involved in iMSCs bone protection and prevention of osteoporosis formation. iMSCs obtained by reprogramming‐induced differentiation had cellular properties similar to those of bone marrow mesenchymal stem cells. The iMSCs could promote the remodelling of bone structure in ovariectomy‐induced osteoporotic mice and affect the changes of several key metabolites in bone and peripheral blood. Some of these metabolites can serve as potential biomarkers and therapeutic targets for iMSCs intervention in osteoporosis. Investigating the effects of iMSCs on osteoporosis and the influence of metabolic pathways will provide new ideas and methods for the clinical treatment of osteoporosis.

This study investigates the expression patterns and clinical relevance of KLHL35 (Kelch-Like Family Member 35) across various cancer types, with a focus on colorectal cancer. Comprehensive analysis of RNA sequencing data from The Cancer Genome Atlas (TCGA) and protein expression data from the Human Protein Atlas (HPA) revealed significant overexpression of KLHL35 in 13 tumor types, including colorectal cancer. Increased KLHL35 expression was associated with poor clinical outcomes, including overall survival (OS), progression-free interval (PFI), and disease-specific survival (DSS). Receiver operating characteristic (ROC) curve analysis suggested promising but exploratory diagnostic value for KLHL35, with area under the curve (AUC) values exceeding 0.9 in colorectal cancer. Functional enrichment analyses suggested potential associations between KLHL35 and cell cycle/apoptosis pathways, while immune infiltration correlations hinted at a possible role in immune microenvironment remodeling. In vitro assays confirmed KLHL35’s role in promoting cancer cell proliferation, invasion, and migration. These findings suggest that KLHL35 could serve as a valuable diagnostic and prognostic biomarker and a potential therapeutic target, particularly in colorectal cancer. While these findings nominate KLHL35 as a candidate for therapeutic targeting, further mechanistic studies are required to validate its function.”

Background and Objectives: Colorectal cancer (CRC) remains a significant cause of cancer-related morbidity and mortality in East Asia. The absolute burden is increasing rapidly, driven largely by demographic change, and varies substantially across countries. However, the extent to which long-term trends, population ageing, and socioeconomic development jointly shape the regional CRC burden has not yet been fully quantified. The objective of the present study is to characterise temporal trends and age-specific patterns in CRC burden, in addition to quantifying the contributions of key drivers of change. Methods: This study is a population-based observational analysis using estimates from the Global Burden of Disease (GBD) 2023 study, covering China, Japan, Mongolia, the Democratic People’s Republic of Korea, and the Republic of Korea from 1990 to 2023. We analyzed incident cases, prevalent cases, deaths, and disability-adjusted life years (DALYs). Age-standardized incidence, prevalence, mortality, and DALY rates were calculated, and their associations with the Socio-demographic Index (SDI) were assessed using Spearman correlation with non-linear curve fitting. Changes in absolute burden were decomposed into contributions from population growth, population ageing, and epidemiological change. Future trends of age-standardized rates to 2050 were projected using autoregressive integrated moving average (ARIMA) models, and temporal changes in mortality trends were evaluated using joinpoint regression. Results: From 1990 to 2023, the absolute numbers of incident cases, prevalent cases, deaths, and DALYs from CRC increased across all countries, while trends in age-standardized rates diverged. The age-standardized incidence rate increased markedly in the Republic of Korea (22.98 to 37.78 per 100,000; EAPC 1.71%) and the Democratic People’s Republic of Korea (13.88 to 22.60 per 100,000; EAPC 1.48%), with more moderate increases in China and Japan and a slight decline in Mongolia. The age-standardized prevalence rate rose substantially, particularly in the Republic of Korea (96.07 to 224.73 per 100,000; EAPC 3.01%). In contrast, age-standardized mortality and DALY rates declined in most countries but increased in the Democratic People’s Republic of Korea. The burden increased steeply with age, especially after 50 years. Significant positive correlations were observed between SDI and all age-standardized rates (ρ = 0.843–0.748, all p < 0.001), with non-linear patterns at higher SDI levels. Decomposition analysis identified population ageing as the primary driver of increasing burden. Projections indicate that the burden will remain high or continue to rise modestly through 2050, with increasing uncertainty. Joinpoint analysis revealed declining mortality trends in China, Japan, and the Republic of Korea, persistent increases in the Democratic People’s Republic of Korea, and a recent upturn in Mongolia. Conclusions: The prevailing burden of non-communicable diseases in East Asia is characterised by an increase in the absolute number of cases, despite concurrent improvements or stabilisation in mortality and DALY rates in several settings. This phenomenon is predominantly driven by population ageing. The presence of strong SDI gradients and adverse trends in the DPRK underscores the necessity for customised strategies, encompassing risk-factor management, equitable expansion of screening programmes, and the augmentation of treatment capacity, with a particular emphasis on adults aged ≥ 50 years, to alleviate the anticipated future burden.