Short-chain fatty acids (SCFAs), the primary metabolites produced by the microbial fermentation of dietary fibers in the gut, have a key role in protecting gut health. Increasing evidence indicates SCFAs can exert effects on distant tissues and organs beyond the gut via blood circulation. Osteoarthritis (OA) is a chronic inflammatory joint disease that severely diminishes the physical function and quality of life. However, effective clinical treatments for OA remain elusive. Recent studies have shown that SCFAs can exert beneficial effects on damaged joints in OA. SCFAs can mitigate OA progression by preserving intestinal barrier function and maintaining the integrity of cartilage and subchondral bone, suggesting that they have substantial potential to be the adjunctive treatment strategy for OA. This review described the SCFAs in the human body and their cellular signaling mechanism, and summarized the multiple effects of SCFAs (especially butyrate, propionate, and acetate) on the prevention and treatment of OA by regulating the gut-joint axis, providing novel insights into their promising clinical applications.

Late-life diseases result from the poorly understood process of senescence (aging), which is largely genetically determined. According to a recently proposed evolutionary physiology-based account, the multifactorial model, senescence is largely caused by evolved but non-adaptive programmatic mechanisms specified by the wild-type (i.e. normal) genome. These act together with disruptions to wild-type function (due e.g. to infectious pathogens, mechanical injury and malnutrition) in a variety of combinations to generate diverse late-life diseases. Here, I explore the utility of this model by testing its capacity to provide an account of one complex, late-life disease, osteoarthritis (OA), and suggest a framework for understanding OA etiology. In this cartilage-focused framework, a core OA disease mechanism is a futile (non-adaptive) developmental program of endochondral ossification, in which hypertrophic articular cartilage chondrocytes alter joint architecture. Programmatic changes prime chondrocytes for futile program activation, which can be triggered by secondary causes of OA (e.g. joint mechanical injury). I suggest that an evolutionary cause of this priming, involving antagonistic pleiotropy, is selection to maximize early-life tissue repair benefits at the expense of late-life programmatic costs.

We aimed to systematically evaluate and analyze the clinical efficacy of oral probiotics in the treatment of knee osteoarthritis (KOA) based on the theory of "gut-joint axis."

We searched PubMed, The Cochrane Library, Embase, China Knowledge Network (CNKI), Wanfang Database, and Wipro Database (CQVIP) databases for clinical randomized controlled trials of oral probiotics for the treatment of KOA. The literature was organized by Note express software, and the quality of the included literature was evaluated according to the Cochrane systematic evaluation method, and meta-analysis was performed using RevMan 5.4 software.

Five randomized controlled trials with 694 participants were included in this study, and the results of the meta-analysis showed that the observation group experienced significant reductions in the Western Ontario and McMaster Universities Osteoarthritis Index total score, visual analog score, and high-sensitivity C-reactive protein level compared to the control group, but did not show significant differences in improvement of stiffness and regulation of body weight.

Oral probiotics had an ameliorative effect on function, pain, and inflammatory response in patients with KOA, but our results need to be validated in future large-scale studies.

The website is https://www.crd.york.ac.uk/PROSPERO/.

Observational studies have shown that the gut microbiota (GM) is associated with bone diseases, particularly calcium-phosphorus metabolic bone diseases, demonstrating the existence of a gut-bone axis. However, whether these associations are causal effects remains to be determined. This study employed bidirectional two-sample Mendelian randomisation (MR) using summary data from Genome-Wide Association Studies (GWAS) of 211 gut microbial taxa and six metabolic bone diseases (osteoporosis, Osteopenia, osteonecrosis, osteomyelitis, hypoparathyroidism and hyperparathyroidism) to explore causal relationships and their directionality. Comprehensive sensitivity analyses were conducted to ensure the robustness of the results, and a false discovery rate-corrected pFDR of < 0.05 was used as a threshold to support strong associations. Additionally, co-localisation analysis was conducted to consolidate the findings. We identified 35 causal relationships between GM and metabolic bone diseases, with 17 exhibiting positive and 18 negative correlations. Furthermore, reverse MR analysis indicated that osteomyelitis was associated with elevated abundance of two GMs (pFDR < 0.05, PP.H4 < 75%). No evidence of horizontal pleiotropy or heterogeneity was observed, and co-localisation analysis further strengthened the evidence for these causal relationships. The study underscores the critical role of GM in influencing bone health through the gut-bone axis, paving the way for future therapeutic interventions targeting the gut-bone axis and offering new directions for research in bone metabolism and diseases.

The microbiota, a complex assembly of microorganisms residing in various body systems, including the gastrointestinal tract, plays a crucial role in influencing various physiological processes in the human body. The dynamic nature of gut microbiota is especially pronounced in children and is influenced by factors like breastfeeding and antibiotic use. Dysbiosis, characterized by alterations in microbiota composition or function, is associated with several pediatric endocrine disorders, such as precocious puberty, polycystic ovarian syndrome, and diabetes mellitus. This review focuses on the intricate relationship between gut microbiota and the pediatric endocrine system. The aim of this narrative review is to critically examine the existing literature to elucidate the impact of gut microbiota on the pediatric endocrine system and associated disorders. Additionally, potential interventions, such as probiotics and current gaps in knowledge, will be discussed. Despite emerging treatments like probiotics, further research is needed to understand and validate their effectiveness in treating pediatric endocrine disorders associated with dysbiosis.

This review examines the strong association between metabolic dysfunction-associated steatotic liver disease (MASLD) and osteoporosis (OP), with a particular focus on the role of gut microbiota in linking these two disorders. Both MASLD and OP are closely linked to metabolic syndrome, and their pathogenesis involves multiple factors, such as inflammatory response, insulin resistance, altered intestinal permeability, and estrogen deficiency. Dysregulation of gut microbiota not only affects hepatic fat accumulation and bone metabolism disorders through metabolites, such as short-chain fatty acids, but also exacerbates systemic chronic inflammation by impairing the intestinal barrier function, thus accelerating the progression of both diseases. This article summarizes recent studies that highlight the central role of gut microbiota as a co-morbid factor in MASLD and OP, offering new perspectives for future diagnostic and therapeutic strategies.

ObjectiveThis study aimed to identify genes and signaling pathways associated with acute cartilage injury using RNA sequencing (RNA-seq).MethodsKnee joint cartilage samples were collected from normal mice and 2 models of acute cartilage injury (non-invasive and groove models) within an 8-hour time limit. RNA-seq revealed differential gene expression between the injury models and controls, with subsequent validation using real-time quantitative polymerase chain reaction (RT-qPCR) for 9 representative genes.ResultsCompared to controls, the non-invasive model showed 36 differentially expressed genes (DEGs) (13 up-regulated, 23 down-regulated), with Gm14648 and Gm35438 showing the most significant upregulation and downregulation, respectively. The groove model exhibited 255 DEGs (13 up-regulated, 23 down-regulated), with Gm14648 and Gm35438 showing the (222 up-regulated, 33 down-regulated). Six overlapping genes were identified between the non-invasive and groove models, including up-regulated genes (Igfn1, Muc6, Hmox1) and down-regulated genes (Pthlh, Cyp1a1, Gm13490), validated by RT-qPCR. Gene ontology (GO) analysis highlighted involvement in environmental information processing and cartilage organ system function, while Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis implicated the JAK-STAT signaling pathway. RT-qPCR and immunohistochemistry confirmed downregulation of Fhl1 in the non-invasive model, supported by Western blotting of p-JAK2/t-JAK2 levels.ConclusionsThis study identifies DEGs (13 up-regulated, 23 down-regulated), with Gm14648 and Gm35438 showing the in acute cartilage injury, suggesting potential therapeutic targets. The role of Fhl1 in cartilage protection via the JAK-STAT pathway warrants further investigation in acute cartilage injury research.

Emerging evidence suggests a link between gut microbiota and intervertebral disc diseases (IDDs); however, the causal relationships remain unclear. This study aimed to evaluate the causal effects of gut microbiota on the risk of cervical disc disorders (CDD), other intervertebral disc disorders (OIDD), pyogenic intervertebral disc infections, and discitis, shedding light on the potential "gut-disc axis".

Genetic variation data for 202 gut microbiota taxa were obtained from the Dutch Microbiome Project, and disease outcome data were sourced from the FinnGen consortium. A Mendelian Randomization (MR) approach was employed to assess causal relationships, using genetic variants as instrumental variables. Sensitivity analyses, including tests for pleiotropy, heterogeneity, and reverse causation, ensured robust findings.

The study identified 20 gut microbial taxa with significant associations to IDDs. Notably, taxa within the Erysipelotrichaceae family showed consistent protective effects against OIDD after Bonferroni correction (P < 0.05). Associations between several species and specific diseases, such as Alistipes senegalensis with CDD and Ruminococcus lactaris with discitis, were also observed. Sensitivity analyses confirmed no evidence of confounding or reverse causation.

This study provides evidence of causal relationships between specific gut microbiota and IDDs, supporting the existence of a "gut-disc axis." The findings suggest that microbial dysbiosis may influence spinal health through systemic inflammation and immune regulation. These insights open new possibilities for microbiota-targeted interventions, such as probiotics or dietary modifications, to prevent or manage IDDs. However, further research is required to validate these therapeutic strategies.

Osteoporosis and osteoarthritis are key diseases of musculoskeletal ageing and are increasing in prevalence and burden with the progressively ageing population worldwide. These conditions are thus particularly common in 'the oldest old', and there are complexities of managing them within the context of extensive multimorbidity, physical and mental disability, and polypharmacy, the rates for all of which are high in this population. In this narrative review, we explore the epidemiology of osteoporosis and osteoarthritis in the oldest old before examining trials and real-world data relating to the pharmacological treatment of these diseases in older adults, including anti-resorptives and bone-forming agents in osteoporosis and symptomatic slow-acting drugs for osteoarthritis, paracetamol, and non-steroidal anti-inflammatory drugs in osteoarthritis, recognising that the oldest old are usually excluded from clinical trials. We then review the potential benefits of nutritional interventions and exercise therapy before highlighting the health economic benefits of interventions for osteoporosis and osteoarthritis. The high prevalence of risk factors for both disease and adverse events associated with treatment in the oldest old mean that careful attention must be paid to the potential benefits of intervention (including fracture risk reduction and improvements in osteoarthritis pain and function) versus the potential harms and adverse effects. Further direct evidence relating to such interventions is urgently needed from future research.

Recent research indicated a strong link between the gut microbiota and osteoarthritis. However, the complex interplay between the gut microbiota, serum metabolites, and the progression of osteoarthritis in affected individuals remains largely unexplored. This study aimed to investigate the characteristics of the gut microbiota and serum metabolites in patients with osteoarthritis.

Participants with either healthy knees or osteoarthritis were enrolled and categorized into healthy control (HC) and osteoarthritis (OA) groups. Fecal and blood samples were collected for 16S rRNA gene sequencing, metabolomic analysis via liquid chromatography-mass spectrometry (LC-MS), and integrated evaluation.

The results showed no significant variation in gut microbiota richness and diversity between the two groups. However, the abundance of Bacteroides plebeius and Faecalibacterium prausnitzii was reduced in the OA group, both of which are known for their potential as next-generation probiotics for human health. Metabolomic analysis indicated that serum metabolites, including pyrogallol and 3-hydroxybutyrate (3HB), were significantly lower in the OA group. These metabolites are known to positively impact osteoarthritis progression and other diseases and demonstrated good diagnostic performance for distinguishing osteoarthritis patients from healthy controls. Correlation analysis revealed a positive correlation between Bacteroides plebeius and Faecalibacterium prausnitzii and between pyrogallol and 3HB.

This study highlighted specific gut microbiota and serum metabolite profiles in osteoarthritis patients, suggesting that the specific changes in bacteria and derived metabolites are closely tied to osteoarthritis progression. This underscores the potential of gut microbiota and serum metabolites as modifiable elements and therapeutic targets for osteoarthritis prevention.

Osteoarthritis (OA) is a chronic, progressive degenerative joint disease that affects the entire synovial joint, leading to the progressive degeneration of articular cartilage. It seriously affects the quality of life and global disability of patients. OA is affected by a variety of factors; the most significant risk factor for OA is age. As individuals age, the risk and severity of OA increase due to the exacerbation of cartilage degeneration and wear and tear. In recent years, research has indicated that the gut microbiota may play a significant role in the aging and OA processes. It is anticipated that regulating the gut microbiota may offer novel approaches to the treatment of OA. The objective of this paper is to examine the relationship between the gut microbiota and senile OA, to investigate the potential mechanisms involved. This review also summarizes the therapeutic strategies related to gut flora in OA management, such as prebiotics and probiotics, diet, exercise, traditional Chinese medicine (TCM) modification, and fecal microbiota transplantation (FMT), highlighting the potential clinical value of gut flora and elucidating the current challenges. The foundation for future research directions is established through the summarization of current research progress.

To investigate the effect of glucocorticoids (GCs) on the risk of readmission in menopausal women with knee osteoarthritis (OA).

The study cohort comprised 80 menopausal women with knee OA treated at a tertiary hospital affiliated with Shanxi Medical University and who underwent follow-up between September 2018 and September 2023. Then the collected longitudinal monitoring data were used to construct a semi-variable coefficient shared Gamma frailty model (VCSGF). Based on the results of this model, we explored the impact of GCs on menopausal women with knee OA and made risk predictions.

The mean patient age at study entry was 64.7 ± 9.3 (range 50-82 years). And during the research, patients were admitted to the hospital a mean of 2.4 ± 1.8 times (range 1-11 times). Compared to patients who have not used the drug, the risk of early readmission in patients who have used GCs was reduced by 96% (HR = 0.04, 95%CI: 0.006 ~ 0.284, [Formula: see text]). This protective effect diminished over time ([Formula: see text]). In addition, the risk of hospital admission with recurrent symptoms was roughly 3.35-fold higher in patients who drink alcohol than in patients who do not (95%CI: 1.661~6.794, [Formula: see text]).

GC use reduced the risk of readmission in menopausal women with knee OA, although this effect diminished over time. Therefore, in patients without further contraindications, GCs may be used in moderation to reduce the readmission risk. In clinical practice, additional research is needed to investigate the timing and appropriate use of GC in the treatment of menopausal women with knee OA, and to develop a more rational program for GC use.

The prevalence of obesity and osteoporosis (OP) represents a significant public health concern on a global scale. A substantial body of evidence indicates that there is a complex relationship between obesity and OP, with a correlation between the occurrence of OP and obesity. In recent years, sirtuins have emerged as a prominent area of interest in the fields of aging and endocrine metabolism. Among the various research avenues exploring the potential of sirtuins, the effects of these proteins on obesity and OP have garnered significant attention from numerous researchers. Sirtuins regulate energy balance and lipid balance, which in turn inhibit the process of adipogenesis. Additionally, sirtuins regulate the balance between osteogenic and osteoblastic activity, which protects against the development of OP. However, no study has yet provided a comprehensive discussion of the relationship between the three: sirtuins, obesity, and OP. This paper will therefore describe the relationship between sirtuins and obesity, the relationship between sirtuins and OP, and a discussion focusing on the possibility of treating OP caused by obesity by targeting sirtuins. This will be based on the common influences on the occurrence of obesity and OP (such as mesenchymal stem cells, gut microbiota, and insulin). Finally, the potential of SIRT1, an important member of sirtuins, in polyphenolic natural products for the treatment of obesity and OP will be presented. This will contribute to a better understanding of the interactions between sirtuins and obesity and bone, which will facilitate the development of new therapeutic strategies for obesity and OP in the future.

Osteoarthritis (OA) is a common progressive degenerative disease. Gut microbiota (GM) and their metabolites have been closely associated with the onset, progression, and pathology of OA. GM and their metabolites may influence the cartilage directly, or indirectly by affecting the gut, the immune system, and the endocrine system. They function through classical pathways in cartilage metabolism and novel pathways that have recently been discovered. Some of them have been used as targets for the prevention and treatment of OA. The current study sought to describe the major pathological signaling pathways in OA chondrocytes and the potential role of gut-related factors in these pathways.

Evidence has revealed that oestrogen deprivation-induced osteolysis is microbiota-dependent and can be treated by probiotics. However, the underlying mechanism require further investigation. This study aims to provide additional evidence supporting the use of probiotics as an adjuvant treatment and to explore the pathophysiology of oestrogen-deprived osteolysis.

Forty-five SD rats were randomly divided into five groups (n = 9). Rats from four groups were ovariectomised and treated with NS, calcium, probiotics, or calcium + probiotics, while one group underwent a sham operation and was treated with NS. The osteometabolic effects were evaluated, and the mechanistic role of the probiotic supplement was explored.

Intragastric administration of Bifidobacterium animalis subsp. lactis LPL-RH (LPL-RH) markedly suppressed osteoclastic activation and bone calcium loss by downregulating TRAP enzymatic activity, the OPG/RANKL ratio, and the downstream signalling pathway RANKL/TRAF6/NF-κB/NFATc1/TRAP in ovariectomised SD rats. LPL-RH also reduced CD4+IL-17 A+ TH17 cells in the bone marrow, the pro-osteoclastogenic cytokine IL-17 A, pro-inflammatory molecules (LPS), and its binding protein (LBP) in the blood. LPL-RH restored intestinal ZO-1, occludin, claudin 2, claudin 12, and claudin 15, which improved ileal histopathology, reduced ileal oxidative stress, and attenuated the LPS-responsive TLR4/MyD88/NF-κB pathway. Furthermore, 16 S rRNA sequencing revealed that LPL-RH altered the faecal microbiome by reducing the relative abundance of S24-7 at the family level and promoting Prevotella and Bacteroides at the genus level.

Collectively, LPL-RH suppressed osteoclastogenesis and osteolysis by modulating type 17 immunity and gut microbiome.

The gut microbiome, a complex ecosystem of microorganisms in the digestive tract, has emerged as a critical factor in human health, influencing metabolic, immune, and neurological functions. This review explores the connection between the gut microbiome and orthopedic health, examining how gut microbes impact bone density, joint integrity, and skeletal health. It highlights mechanisms linking gut dysbiosis to inflammation in conditions such as rheumatoid arthritis and osteoarthritis, suggesting microbiome modulation as a potential therapeutic strategy. Key findings include the microbiome's role in bone metabolism through hormone regulation and production of short-chain fatty acids, crucial for mineral absorption. The review also considers the effects of diet, probiotics, and fecal microbiota transplantation on gut microbiome composition and their implications for orthopedic health. While promising, challenges in translating microbiome research into clinical practice persist, necessitating further exploration and ethical consideration of microbiome-based therapies. This interdisciplinary research aims to link digestive health with musculoskeletal integrity, offering new insights into the prevention and management of bone and joint diseases.

Osteoarthritis (OA) is the most prevalent degenerative arthritis disease linked to aging, obesity, diet, and accumulation of octacalcium phosphate (OCP) crystals in joints. Current research has focused on inflammation and chondrocytes apoptosis as underlying OA mechanisms. Inflammatory cytokines like IL-1β activate matrix metalloproteinase-13 (MMP-13) and aggrecanase (the member of A Disintegrin and Metalloproteinase with Thrombospondin motifs family, ADAMTS), leading to cartilage matrix degradation. The NLRP3 inflammasome also contributes to OA pathogenesis by maturing IL-1β. Natural products like chondroitin sulfate oligosaccharides (oligo-CS) show promise in OA treatment by inhibiting inflammation. Our study evaluates the protective effects of oligo-CS against OA by targeting NLRP3 inflammation. Stimulating human SW1353 chondrocytes and human mononuclear macrophage THP-1 cells with OCP showed increased NLRP3 inflammation initiation, NF-κB pathway activation, and the production of inflammatory cytokines (IL-1β, IL-6) and the metabolic index (MMP-13, ADAMTS-5), leading to cartilage matrix degradation. However, oligo-CS treatment significantly reduced inflammation. In a 28-day in vivo study with C57BL/6 female mice, OCP was injected into their right knee and oligo-CS was orally administered. The OCP group exhibited significant joint space narrowing and chondrocyte loss, while the oligo-CS group maintained cartilage integrity. Oligo-CS groups also regulated gut microbiota composition to a healthier state. Taken together, our findings suggest that oligo-CS can be considered as a protective compound against OA.

Intra-articular injections of ozone and hyaluronic acid (HA) are routinely performed for the management of knee osteoarthritis. The present meta-analysis compared intra-articular injections of HA versus ozone in patients with knee osteoarthritis (OA) in patient-reported outcome measures (PROMs). The outcomes of interest were to determine if intra-articular ozone injections show comparable visual analogue scale (VAS) and Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) scores compared to intra-articular HA injections.

This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the 2020 PRISMA statement. In January 2024, the following databases were accessed: PubMed, Web of Science, Google Scholar, and Embase. All the randomised controlled trials (RCTs) comparing intra-articular HA versus ozone injections in patients with knee OA were accessed. Only studies which clearly stated that injections were performed in patients with knee OA were considered. Data concerning the VAS and WOMAC were retrieved at baseline and the last follow-up. Studies with a follow-up shorter than 4 months or longer than 6 months were not included.

Data from 424 patients were collected. 74% (314 of 424 patients) were women. The mean age of the patients was 61.1 ± 4.5 years, and the mean BMI was 27.8 ± 0.8 kg/m2. Compatibility was found in the mean age, mean BMI, PROMs, and the percentage of women. No difference was found in VAS at follow-up (P = 0.4).

The current level I evidence suggests that ozone and HA intra-articular injections achieve similar pain control between 4 and 6 months of follow-up.

Level I.

This comprehensive review examines the relationship between osteoarthritis (OA) and osteoporosis (OP), two common disorders in the elderly. OA involves joint cartilage degeneration and pain, while OP leads to fractures due to reduced bone mass. Despite different pathologies, both conditions share risk factors such as age and genetics. Studies reveal mixed results: some show higher bone mineral density (BMD) in OA patients, suggesting an inverse relationship, while others find no significant link. Proposed mechanisms include mechanical loading, bone remodeling, and inflammation. Clinical strategies focus on maintaining bone health in OA and monitoring joint health in OP, with treatments like bisphosphonates and exercise. Understanding these interactions is crucial for developing integrated treatments to improve patient outcomes and quality of life. Further research is needed to clarify these complex mechanisms.

In degenerative joint disease like osteoarthritis (OA), bioactive compounds like resveratrol, epigallocatechin gallate, curcumin, and other polyphenols often target various signalling pathways, including NFκB, TGFβ, and Wnt/β-catenin by executing epigenetic-modifying activities. Epigenetic modulation can target genes of disease pathophysiology via histone modification, promoter DNA methylation, and non-coding RNA expression, some of which are directly involved in OA but have been less explored. OA patients often seek options that can improve the quality of their life in addition to existing treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). Although bioactive and natural compounds exhibit therapeutic potential against OA, several disadvantages loom, like insolubility and poor bioavailability. Nanoformulated bioactive compounds promise a better way to alleviate OA since they also control systemic events, including metabolic, immunological, and inflammatory responses, by modulating host gut microbiota that can regulate OA pathogenesis. Recent data suggest gut dysbiosis in OA. However, limited evidence is available on the role of bioactive compounds as epigenetic and gut modulators in ameliorating OA. Moreover, it is not known whether the effects of polyphenolic bioactive compounds on gut microbial response are mediated by epigenetic modulatory activities in OA. This narrative review highlights the nanotherapeutic strategies utilizing bioactive compounds, reporting their effects on chondrocyte growth, metabolism, and epigenetic modifications in osteoarthritis amelioration.

Degenerative joint disease osteoarthritis (OA) is characterized by the degeneration of cartilage, synovial inflammation and low-grade systemic inflammation in association with microbial dysbiosis and intestinal barrier defects. Butyrate is known for its anti-inflammatory and barrier protective effects and might benefit OA patients. In a double-blind placebo-controlled randomized trial, the effects of four to five weeks of oral treatment with sustained-release (SR) butyrate tablets (600 mg/day) on systemic inflammation and immune function were studied in hand OA patients. Serum markers for systemic inflammation and lipopolysaccharide (LPS) leakage were measured and ex vivo stimulation of whole blood or peripheral blood mononuclear cells (PBMCs) was performed at baseline and after treatment. Butyrate treatment did not affect the serum markers nor the cytokine release of ex vivo LPS-stimulated whole blood or PBMCs nor the phenotype of restimulated monocytes. By contrast, butyrate treatment reduced the percentage of activated T helper (Th) cells and the Th17/Treg ratio in αCD3/CD28-activated PBMCs, though cytokine release upon stimulation remained unaffected. Nevertheless, the percentage of CD4+IL9+ cells was reduced by butyrate as compared to the placebo. In both groups, the frequency of Th1, Treg, Th17, activated Th17, CD4+IFNγ+ and CD4+TNFα+ cells was reduced. This study shows a proof of principle of some immunomodulatory effects using a SR butyrate treatment in hand OA patients. The inflammatory phenotype of Th cells was reduced, as indicated by a reduced percentage of Th9 cells, activated Th cells and improved Th17/Treg balance in ex vivo αCD3/CD28-activated PBMCs. Future studies are warranted to further optimize the butyrate dose regime to ameliorate inflammation in OA patients.

In recent years, systemic inflammation has emerged as a pivotal player in the development and progression of various degenerative diseases. This complex, chronic inflammatory state, often undetected, can have far-reaching consequences for the body's physiology. At the molecular level, markers such as C-reactive protein, cytokines and other inflammatory mediators serve as indicators of systemic inflammation and often act as predictors of numerous musculoskeletal diseases and even certain forms of cancer. The concept of 'meta-inflammation', specifically referring to metabolically triggered inflammation, allows healthcare professionals to understand inflammatory responses in patients with metabolic syndrome. Driven by nutrient excess and the expansion of adipose tissue, meta-inflammation is closely associated with insulin resistance, further propagating the metabolic dysfunction observed in many Western societies. Wound persistence, on the other hand, exacerbates the detrimental effects of prolonged inflammation at the local level. Acute inflammation is a beneficial and essential process for wound healing and infection control. However, when inflammation fails to resolve, it can impede the healing process, leading to chronic wounds, excessive scarring and even the activation of fibrotic pathways. This approach significantly reduces the efficacy of regenerative biological therapies. Our review focuses on the vital role of proteins, vitamins and minerals in collagen synthesis and cell proliferation for tissue healing. We also examine hormonal influences on regeneration, noting the negative effects of imbalances, and emphasize glucose regulation's importance in creating a stable environment for chronic wound healing.

Gut microbiome alterations resulting in inflammatory responses have been implicated in many distant effects on different organs. However, its influence on disc health is still not fully investigated.

Our objective was to document the gut biome in healthy volunteers and patients with disc degeneration and to understand the role of gut dysbiosis on human disc health.

Experimental case-control study.

We included 40 patients with disc degeneration (DG) and 20 healthy volunteers (HV). HV comprised of age groups 30 to 60 years with no known record of back pain and no clinical comorbidities, with normal MRI. Diseased group (DG) were patients in the same age group undergoing surgery for disc disease (disc herniation-25; discogenic stenosis-15) and without instability (with Modic-20; and non-Modic-20).

N/A.

We analyzed 16S V3-V4 rDNA gut metagenome from 20 healthy volunteers (HV) and compared the top signature genera from 40 patients with disc degeneration (DG) across Modic and non-Modic groups. Norgen Stool DNA Kit was used for DNA extraction from ∼200 mg of each faecal sample collected using the Norgen Stool Collection Kit.16S V3-V4 rDNA amplicons were generated with universal bacterial primers 341F and 806R and amplified with Q5 High-Fidelity DNA Polymerase. Libraries were sequenced with 250×2 PE to an average of 0.1 million raw reads per sample (Illumina Novaseq 6000). Demultiplexed raw data was assessed with FastQC, and adapter trimmed reads >Q30 reads were processed in the QIME2 pipeline. Serum C-reactive protein (CRP) was measured by the immunoturbimetry method and Fatty acid-binding protein 5 (FABP5) was measured in albumin-globulin-depleted plasma through global proteome analysis.

We observed significant gut dysbiosis between HV and DG and also between the Modic and non-Modic groups. In the Modic group, commensals Bifidobacterium and Ruminococcus were significantly depleted, while pathobionts Streptococcus, Prevotella, and Butryvibrio were enriched. Firmicutes/Bacteroidetes ratio was decreased in DG (Modic-0.62, non-Modic-0.43) compared to HV (0.70). Bacteria-producing beneficial short-chain fatty acids were also depleted in DG. Elevated serum CRP and increased FABP5 were observed in DG.

The study revealed gut dysbiosis, an altered Firmicutes/Bacteroidetes ratio, reduced SCFA-producing bacteria, and increased systemic and local inflammation in association with disc disease, especially in Modic changes. The findings have considerable importance for our understanding and prevention of disc degeneration.

Although recent observational studies and clinical trials have indicated a strong association between the gut microbiota and spinal stenosis diseases, the causal relationship between them remains unclear.

Based on large-scale genome-wide association studies, we employed two-sample Mendelian randomization (MR) to analyse the causal relationships between the gut microbiota (GM) and 3 spinal stenosis diseases: adolescent idiopathic scoliosis (AIS), lumbar spondylolisthesis (LS), and spinal stenosis (SS). MR analysis was performed using the inverse variance weighting (IVW) method as the primary approach, supplemented by MR‒Egger regression, weighted median, and weighted mode analyses. MR-PRESSO and MR‒Egger regression were employed to assess horizontal pleiotropy. Cochran's Q test was used to evaluate heterogeneity. Further leave-one-out sensitivity analysis was conducted to ascertain the reliability of the causal relationships.

The IVW method identified 9 gut microbiota taxa (9 genera) that were causally related to AIS, 14 taxa (4 phyla, 2 classes, 2 orders, 1 family, and 5 genera) to LS, and 4 taxa (2 classes, 1 order, and 1 genus) to SS. The Cochrane Q test results did not indicate heterogeneity. Moreover, both the MR‒Egger intercept test and the MR-PRESSO global test demonstrated that our findings were robust against potential horizontal pleiotropy. Furthermore, leave-one-out analysis provided additional evidence supporting the reliability of our identified causal relationships.

Our findings have substantiated the potential causal impact of specific GM taxa on AIS, LS, and SS, thereby offering novel insights into the mechanisms mediated by the gut microbiota in these three diseases and laying the foundation for targeted preventive measures in further research.

Osteoarthritis (OA) is a prevalent joint disorder and the most common form of arthritis, affecting approximately 500 million people worldwide, or about 7% of the global population. Its pathogenesis involves a complex interplay between metabolic dysfunction and gut microbiome (GM) alterations. This review explores the relationship between metabolic disorders-such as obesity, diabetes, and dyslipidemia-and OA, highlighting their shared risk factors, including aging, sedentary lifestyle, and dietary habits. We further explore the role of GM dysbiosis in OA, elucidating how systemic inflammation, oxidative stress, and immune dysregulation driven by metabolic dysfunction and altered microbial metabolites contribute to OA progression. Additionally, the concept of "leaky gut syndrome" is discussed, illustrating how compromised gut barrier function exacerbates systemic and local joint inflammation. Therapeutic strategies targeting metabolic dysfunction and GM composition, including lifestyle interventions, pharmacological and non-pharmacological factors, and microbiota-targeted therapies, are reviewed for their potential to mitigate OA progression. Future research directions emphasize the importance of identifying novel biomarkers for OA risk and treatment response, adopting personalized treatment approaches, and integrating multiomics data to enhance our understanding of the metabolic-GM-OA connection and advance precision medicine in OA management.

The nuclear factor-κB (NF-κB) signalling pathway exists in a variety of cells and is involved in the gene regulation of various physiological and pathological processes such as inflammation, immunity, cell proliferation and apoptosis. It has been shown that this signaling pathway is also involved in numerous events associated with osteoarthritis, including chondrocyte catabolism, chondrocyte survival, and synovial inflammation. SRY-related high mobility group-box 9(SOX9) is the "master regulator" of chondrocytes and one of the key transcription factors that maintain chondrocyte phenotype and cartilage homeostasis. NF-κB can positively regulate the expression of SOX9 by directly binding to its promoter region, and play a role in the formation and development of chondrocytes. This article reviews the regulatory effect of the NF-κB-SOX9 signaling axis on osteoarthritis.

The integration of telehealth-supported programs in chronic disease management has become increasingly common. However, its effectiveness for individuals with knee osteoarthritis (KOA) remains unclear.

This study aimed to assess the effectiveness of telehealth-supported exercise or physical activity programs for individuals with KOA.

A comprehensive literature search encompassing Embase, MEDLINE, CENTRAL, Web of Science, PubMed, Scopus, PEDro, GreyNet, and medRxiv from inception to September 2023 was conducted to identify randomized controlled trials comparing telehealth-supported exercise or physical activity programs to a control condition for KOA. Data were extracted and qualitatively synthesized across eligible studies, and a meta-analysis was performed to evaluate the effects. The study was reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020.

In total, 23 studies met eligibility criteria, with 20 included in the meta-analysis. Results showed that telehealth-supported exercise or physical activity programs reduced pain (g=-0.39; 95% CI -0.67 to -0.11; P<.001), improved physical activity (g=0.13; 95% CI 0.03-0.23; P=.01), and enhanced physical function (g=-0.51; 95% CI -0.98 to -0.05; P=.03). Moreover, significant improvements in quality of life (g=0.25; 95% CI 0.14-0.36; P<.001), self-efficacy for pain (g=0.72; 95% CI 0.53-0.91; P<.001), and global improvement (odds ratio 2.69, 95% CI 1.41-5.15; P<.001) were observed. However, self-efficacy for physical function (g=0.14; 95% CI -0.26 to 0.53; P=.50) showed insignificant improvements. Subgroup analyses based on the World Health Organization classification of digital health (pain: χ22=6.5; P=.04 and physical function: χ22=6.4; P=.04), the type of teletechnology in the intervention group (pain: χ24=4.8; P=.31 and function: χ24=13.0; P=.01), and active or inactive controls (pain: χ21=5.3; P=.02 and physical function: χ21=3.4; P=.07) showed significant subgroup differences.

Telehealth-supported exercise or physical activity programs might reduce knee pain and improve physical activity, physical function, quality of life, self-efficacy, and global improvement in individuals with KOA. Future research should consider longer implementation durations and assess the feasibility of incorporating wearables and standardized components into large-scale interventions to evaluate the effects.

PROSPERO CRD42022359658; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=359658.

Knee osteoarthritis (KOA) is a prevalent chronic condition associated with significant pain, disability, and healthcare costs, particularly among the elderly population. Despite the considerable burden of KOA, effective treatment options for managing the condition's underlying causes remain limited. This case-control study aims to investigate the relationship between dietary total antioxidant capacity (DTAC) and knee osteoarthritis.

This case-control study was conducted on 105 patients with confirmed KOA and 210 controls. KOA was diagnosed based on the American College of Rheumatology criteria. Dietary total antioxidant capacity (DTAC) was calculated based on the ferric-reducing antioxidant power method.

The mean age and BMI of the participants were 53.6 ± 8.8 years old and 27.3 ± 2.7 kg/m2, respectively. The study participant's DTAC score ranged from 3.56 to 25.32 with a mean and SD of 12.46 ± 5.12. In the crude model, individuals in the highest quartile of DTAC score had 71% lower odds of having knee osteoarthritis compared to those in the first quartile (OR: 0.29, 95%CI: 0.15 to 0.58, P-trend < 0.001). These associations remained significant after adjustment for potential confounders including age, sex, energy intake, family history of osteoarthritis, vitamin D and calcium use, physical activity level, cigarette smoking and BMI. Although the odds of having knee osteoarthritis decreased with increasing quartiles of DTAC in both sexes, this relationship was stronger among males than females.

The results of this study showed that there was an inverse correlation between DTAC and KOA among the Iranian patients with KOA.

Osteoarthritis (OA) is one of the most common musculoskeletal disorders. Recently, research has focused on the role of intestinal microbiome dysbiosis in OA. The aim of this study was to systematically review randomized intervention clinical studies investigating the effect of probiotics on the management of OA-related pain and inflammation. Pre-clinical studies and non-randomized trials were excluded. A literature search was conducted using MEDLINE, EMBASE, and Web of Science. Study quality was assessed with the Cochrane risk of bias (RoB2) tool and the Risk of Bias in N-of-1 Trials (RoBiNT) scale. RevMan was used for the meta-analysis. Outcome measures assessed self-reported pain, stiffness and impediment, and serum hs-CRP. Three studies, with 501 participants, were considered eligible for qualitative synthesis and meta-analysis. A significant reduction in symptoms across all outcomes measured, except stiffness, was evident with Lactobacillus casei Shirota. However, all other probiotics reviewed did not seem to have any effect on the measured outcomes. Pre-clinical evidence, along with the RCTs reviewed, suggests that probiotics of the Lactobacillus strains might be of use for managing pain and inflammation in OA. Considering the small number of studies included in the present review and the possible risk of bias, we conclude that further studies on the role of probiotics in humans with OA are warranted.

Extensive research efforts have been dedicated to elucidating the intricate pathways by which gastrointestinal microbiota and their metabolites exert influence on the processes of bone formation. Nonetheless, a notable gap exists in the literature concerning a bibliometric analysis of research trends at the nexus of gastrointestinal microbiota and bone metabolism.

To address this scholarly void, the present study employs a suite of bibliometric tools including online platforms, CiteSpace and VOSviewer to scrutinize the pertinent literature in the realm of gastrointestinal microbiota and bone metabolism.

Examination of the temporal distribution of publications spanning from 2000 to 2023 reveals a discernible upward trajectory in research output, characterized by an average annual growth rate of 19.2%. Notably, China and the United States emerge as primary contributors. Predominant among contributing institutions are Emory University, Harvard University, and the University of California. Pacifici R from Emory University contributed the most research with 15 publications. In the realm of academic journals, Nutrients emerges as the foremost publisher, followed closely by Frontiers in Microbiology and PLOS One. And PLOS One attains the highest average citations of 32.48. Analysis of highly cited papers underscores a burgeoning interest in the therapeutic potential of probiotics or probiotic blends in modulating bone metabolism by augmenting host immune responses. Notably, significant research attention has coalesced around the therapeutic interventions of probiotics, particularly Lactobacillus reuteri, in osteoporosis, as well as the role of gastrointestinal microbiota in the etiology and progression of osteoarthritis. Keyword analysis reveals prevalent terms including gut microbiota, osteoporosis, bone density, probiotics, inflammation, SCFAs, metabolism, osteoarthritis, calcium absorption, obesity, double-blind, prebiotics, mechanisms, postmenopausal women, supplementation, risk factors, oxidative stress, and immune system. Future research endeavors warrant a nuanced exploration of topics such as inflammation, obesity, SCFAs, postmenopausal osteoporosis, skeletal muscle, oxidative stress, double-blind trials, and pathogenic mechanisms. In summary, this study presents a comprehensive bibliometric analysis of global research on the interplay between gastrointestinal microbiota and bone metabolism, offering valuable insights for scholars, particularly nascent researchers, embarking on analogous investigations within this domain.

To understand the impact of individual preferences for specific dietary items on OA, and to help inform the development of effective and targeted OA prevention and management strategies, we performed a Mendelian randomization analysis between dietary preferences and osteoarthritis.

This study utilized genetic data from the UK Biobank to investigate the association between OA and 21 different common dietary items. Instrumental variables representing European populations were carefully selected based on their genetic significance and linkage disequilibrium. In cases where a dietary item had few relevant genetic markers, a more lenient selection threshold was applied. To prevent bias, the analysis excluded single nucleotide polymorphisms (SNPs) associated with factors such as body mass index (BMI) and cholesterol. Using inverse-variance weighting (IVW) and Mendelian randomization, significant associations were detected between certain dietary items and OA.

Using Mendelian randomization to examine the relationship between 21 different dietary items and OA, significant associations were found for coffee, peas, watercress, and cheese, where the first two had a promoting effect and the last two an inhibiting effect on OA. Due to heterogeneity in the test results for cheese, a random IVW representation was used. The results of sensitivity analysis showed no significant heterogeneity or horizontal pleiotropy in the selected SNPS, demonstrating the reliability of Mendelian randomization analysis.

This study identified coffee, peas, watercress, and cheese as food items that may have significant dietary effects on osteoarthritis. This information may be useful to consider in the development of OA management strategies.

Osteoarthritis (OA) is a common degenerative joint disease that can cause severe pain, motor dysfunction, and even disability. A growing body of research indicates that gut microbiota and their associated metabolites are key players in maintaining bone health and in the progression of OA. Short-chain fatty acids (SCFAs) are a series of active metabolites that widely participate in bone homeostasis. Gold nanoparticles (GNPs) with outstanding anti-bacterial and anti-inflammatory properties, have been demonstrated to ameliorate excessive bone loss during the progression of osteoporosis (OP) and rheumatoid arthritis (RA). However, the protective effects of GNPs on OA progression are not clear. Here, we observed that GNPs significantly alleviated anterior cruciate ligament transection (ACLT)-induced OA in a gut microbiota-dependent manner. 16S rDNA gene sequencing showed that GNPs changed gut microbial diversity and structure, which manifested as an increase in the abundance of Akkermansia and Lactobacillus. Additionally, GNPs increased levels of SCFAs (such as butyric acid), which could have improved bone destruction by reducing the inflammatory response. Notably, GNPs modulated the dynamic balance of M1/M2 macrophages, and increased the serum levels of anti-inflammatory cytokines such as IL-10. To sum up, our study indicated that GNPs exhibited anti-osteoarthritis effects via modulating the interaction of "microbiota-gut-joint" axis, which might provide promising therapeutic strategies for OA.

The phrase "skin as a mirror of internal medicine," which means that the skin reflects many of the diseases of the internal organs, is a well-known notion. Despite the phenotypic differences between the soft skin and hard bone, the skin and bone are highly associated. Skin and bone consist of fibroblasts and osteoblasts, respectively, which secrete collagen and are involved in synthesis, while Langerhans cells and osteoclasts control turnover. Moreover, the quality and quantity of collagen in the skin and bone may be modified by aging, inflammation, estrogen, diabetes, and glucocorticoids. Skin and bone collagen are pathologically modified by aging, drugs, and metabolic diseases, such as diabetes. The structural similarities between the skin and bone and the crosstalk controlling their mutual pathological effects have led to the advocacy of the skin-bone axis. Thus, the skin may mirror the health of the bones and conversely, the condition of the skin may be reflected in the bones. From the perspective of the skin-bone axis, the similarities between skin and bone anatomy, function, and pathology, as well as the crosstalk between the two, are discussed in this review. A thorough elucidation of the pathways governing the skin-bone axis crosstalk would enhance our understanding of disease pathophysiology, facilitating the development of new diagnostics and therapies for skin collagen-induced bone disease and of new osteoporosis diagnostics and therapies that enhance skin collagen to increase bone quality and density.

Chondroitin sulfate (CS) has widely been used as a symptomatic slow-acting drug or a dietary supplement for the treatment and prevention of osteoarthritis. However, CS could not be absorbed after oral intake due to its polyanionic nature and large molecular weight. Gut microbiota has recently been proposed to play a pivotal role in the metabolism of drugs and nutrients. Nonetheless, how CS is degraded by the human gut microbiota has not been fully characterized. In the present study, we demonstrated that each human gut microbiota was characterized with a unique capability for CS degradation. Degradation and fermentation of CS by the human gut microbiota produced significant amounts of unsaturated CS oligosaccharides (CSOSs) and short-chain fatty acids. To uncover which microbes were responsible for CS degradation, we isolated a total of 586 bacterial strains with a potential CS-degrading capability from 23 human fecal samples. Bacteroides salyersiae was a potent species for CS degradation in the human gut microbiota and produced the highest amount of CSOSs as compared to other well-recognized CS-degraders, including Bacteroides finegoldii, Bacteroides thetaiotaomicron, Bacteroides xylanisolvens, and Bacteroides ovatus. Genomic analysis suggested that B. salyersiae was armed with multiple carbohydrate-active enzymes that could potentially degrade CS into CSOSs. By using a spent medium assay, we further demonstrated that the unsaturated tetrasaccharide (udp4) produced by the primary degrader B. salyersiae could serve as a "public goods" molecule for the growth of Bacteroides stercoris, a secondary CS-degrader that was proficient at fermenting CSOSs but not CS. Taken together, our study provides insights into the metabolism of CS by the human gut microbiota, which has promising implications for the development of medical and nutritional therapies for osteoarthritis. Video Abstract.

Bone aging is characterized by an imbalance in the physiological and pathological processes of osteogenesis, osteoclastogenesis, adipogenesis, and chondrogenesis, resulting in exacerbated bone loss and the development of age-related bone diseases, including osteoporosis, osteoarthritis, rheumatoid arthritis, and periodontitis. Inflammaging, a novel concept in the field of aging research, pertains to the persistent and gradual escalation of pro-inflammatory reactions during the aging process. This phenomenon is distinguished by its low intensity, systemic nature, absence of symptoms, and potential for management. The mechanisms by which inflammaging contribute to age-related chronic diseases, particularly in the context of age-related bone diseases, remain unclear. The precise manner in which systemic inflammation induces bone aging and consequently contributes to the development of age-related bone diseases has yet to be fully elucidated. This article primarily examines the mechanisms underlying inflammaging and its association with age-related bone diseases, to elucidate the potential mechanisms of inflammaging in age-related bone diseases and offer insights for developing preventive and therapeutic strategies for such conditions.