Search Results (506)

Proper joint function has a significant impact on people’s quality of life. Joints are the point of connection between two or more bones and consist of at least three elements: joint surfaces, the joint capsule, and the joint cavity. Joint diseases are a serious social problem. Risk factors for the development of these diseases include overweight and obesity, gender, and intestinal microbiome disorders. Another factor that is considered to influence joint diseases is trace elements. Under normal conditions, elements such as iron (Fe), copper (Cu), cobalt (Co), iodine (I), manganese (Mn), zinc (Zn), silver (Ag), cadmium (Cd), mercury (Hg), lead (Pb), nickel (Ni) selenium (Se), boron (B), and silicon (Si) are part of enzymes involved in reactions that determine the proper functioning of cells, regulate redox metabolism, and determine the maturation of cells that build joint components. However, when the normal concentration of the above-mentioned elements is disturbed and toxic elements are present, dangerous joint diseases can develop. In this article, we focus on the role of trace elements in joint function. We describe the molecular mechanisms that explain their interaction with chondrocytes, osteocytes, osteoblasts, osteoclasts, and synoviocytes, as well as their proliferation, apoptosis, and extracellular matrix synthesis. We also focus on the role of these trace elements in the pathogenesis of joint diseases: rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and systemic lupus erythematosus (SLE). We describe the roles of increased or decreased concentrations of individual elements in the pathogenesis and development of joint diseases and their impact on inflammation and disease progression, referring to molecular mechanisms. We also discuss their potential application in the treatment of joint diseases. Full article

Osteoclastogenesis—the activation and differentiation of osteoclasts—is one of the pivotal processes of bone remodeling and is regulated by RANKL/RANK signaling, the decoy function of osteoprotegerin (OPG), and a cascade of pro- and anti-inflammatory cytokines. The disruption of this balance leads to pathological bone loss in diseases such as osteoporosis and rheumatoid arthritis. FFAR4 (Free Fatty Acid Receptor 4), a G protein-coupled receptor for long-chain omega-3 fatty acids, has been confirmed as a key mediator of metabolic and anti-inflammatory effects. This review focuses on how FFAR4 acts as the selective receptor for the omega-3 fatty acid docosahexaenoic acid (DHA). It activates two divergent signaling pathways. The Gαq-dependent cascade facilitates intracellular calcium mobilization and ERK1/2 activation. Meanwhile, β-arrestin-2 recruitment inhibits NF-κB. These collective actions reshape the cytokine environment. In macrophages, DHA–FFAR4 signaling lowers the levels of TNF-α, interleukin-6 (IL-6), and IL-1β while increasing IL-10 secretion. Consequently, the activation of NFATc1 and NF-κB p65 is profoundly suppressed under TNF-α or RANKL stimulation. Additionally, DHA modulates the RANKL/OPG axis in osteoblastic cells by suppressing RANKL expression, thereby reducing osteoclast differentiation in an inflammatory mouse model. Full article

Background/Objectives: Glucocorticoids (GCs) are frequently prescribed to control disease in Rheumatoid Arthritis (RA). However, long-term GC therapy with high daily doses is associated with bone involvement, which is considered the main extra-articular complication of RA. The trabecular bone score (TBS) has proven useful in assessing vertebral trabecular bone quality and fracture risk. To identify whether the long-term treatment of low doses of GCs are associated with low vertebral TBS in RA patients. Methods: A cross-sectional study, including 203 women with RA (ACR, 1987). Clinical, epidemiologic, and therapeutic variables were assessed. We identified the current daily dose, duration, and cumulative dose of GCs. Vertebral bone quality was assessed by TBS. Low vertebral trabecular bone quality was defined as TBS ≤ 1.300. Multivariate logistic regression analyses were used to identify risk factors of low TBS. Results: Prevalence of low TBS in RA women was 52%. RA + low TBS were older (61.9 vs. 55.5, p < 0.001) and had higher prevalence of menopause (90% vs. 75%, p = 0.004), hypertension (50% vs. 34%, p ≤ 0.02), and diabetes mellitus (13% vs. 4%, p = 0.02). There were no associations between GC use, neither doses or cumulative doses, and TBS. Multivariate analyses showed the following: age (OR: 1.05, 95% CI: 1.02–1.08) and the presence of diabetes mellitus (OR: 3.30, 95% CI: 1.03–10.60) were associated with a high risk of low vertebral trabecular bone quality in RA. Conclusions: Half of the RA patients had low trabecular bone quality. Older age and diabetes mellitus are important risk factors for low trabecular bone quality in RA. These findings should give alert to early detection of low TBS, establishing strategies aimed at avoiding the consequences of this complication, including vertebral fractures. Full article

Background: Recurrent anterior shoulder instability is a common problem and may be associated with glenoid bone defects. Surgical procedures, including Latarjet, are the usual treatment for anterior shoulder instability, associated with significant glenoid bone defects. The aim of this study was to evaluate the clinical outcome and glenohumeral arthritis progression in patients with recurrent anterior shoulder instability and significant bone loss treated by a modified Latarjet procedure. Methods: From July 2018 to November 2021, a prospective observational case series was carried out on 21 patients with recurrent anterior shoulder instability associated with significant bone defects treated by a modified Latarjet procedure in which the coracoid process was rotated 90° on its longitudinal axis and the subscapularis muscle was horizontally split. Patients with a glenoid defect of more than 21% were included. Post-operatively, the patients were clinically assessed using modified Rowe scoring. Glenohumeral arthritis, graft position, union, and resorption were radiologically evaluated. Results: The mean age at the time of surgery was 28.52 ± 8.0 (range: 19–45) years. The mean number of dislocations was 18.33 ± 8.67 (range: 6–35) times. The mean glenoid defect size was 26.19 ± 4.85 (range: 21–37) % and Hill–Sachs lesions were off-track in 19 cases. The mean follow-up period was 30.67 ± 7.53 (range: 16–40) months. Eighteen patients (85.7%) showed good to excellent results. The mean modified Rowe score was 85.00 ± 18.77 (range: 30–100) points. The mean external rotation loss was 8.09 ± 5.11° (range: 0–20°). No cases of recurrent instability were observed, and there was no progression of glenohumeral arthritis. Conclusions: The modified Latarjet is an effective and reliable surgical option to treat traumatic anterior shoulder instability with significant bone loss. Most of the reported complications associated with this procedure did not affect the functional outcome. Full article

This study investigated the effects of Bothrops moojeni (B. moojeni) venom and its high- (HMM) and low-molecular mass (LMM) fractions on human osteoclast (OC) differentiation and function in vitro, aiming to identify novel therapeutics for bone disorders. Venom preparations were applied at 5 µg/mL (crude venom and HMM) or 1 µg/mL (LMM) from day 4 of peripheral blood mononuclear cell (PBMC) differentiation through terminal OC formation, enabling evaluation across early differentiation, fusion, and maturation stages. RNA sequencing revealed 7793 genes common to all experimental groups, with unique gene expression signatures of 149 (control), 221 (HMM), 248 (crude venom), and 60 (LMM) genes, reflecting distinct molecular responses. The negative control PBMC group exhibited 1013 unique genes enriched in immune-related pathways, consistent with their undifferentiated state. Crude venom induced the broadest transcriptional modulation, upregulating key fusion (CD47) and resorption (CTSK) genes, and altering markers of OC differentiation. The HMM fraction predominantly influenced inflammatory and osteoclastogenic pathways, notably TNF and NF-κB signaling, while the LMM fraction selectively regulated fusion-related genes (e.g., CD44) and immune pathways, indicating targeted modulation of OC activity. Cytokine profiling showed that crude venom and HMM suppressed osteoclastogenic cytokines such as IL-1β and IL-6, supporting their potential use in inflammatory bone diseases. Pathway enrichment analyses confirmed these differential effects on immune response and bone resorption mechanisms. Together, these results demonstrate that B. moojeni venom and its fractions differentially impact OC biology, with crude venom exerting broad effects and HMM and LMM fractions offering more specific modulation. Future studies will isolate bioactive components and assess therapeutic efficacy in animal models of osteoporosis and rheumatoid arthritis. Full article

Osteoclasts, which are derived from myeloid precursors, are essential for physiologic bone remodeling but also mediate pathological bone loss in inflammatory diseases such as periodontitis and rheumatoid arthritis. Lysine-specific demethylase (LSD1/KDM1A) is a histone demethylase that modulates the chromatin landscape via demethylation of H3K4me1/2 and H3K9me1/2, thereby regulating the expression of genes essential for deciding cell fate. We previously demonstrated that myeloid-specific deletion of LSD1 (LSD1LysM-Cre) disrupts osteoclast differentiation, leading to enhanced BV/TV under physiological conditions. In this study, we show that LSD1LysM-Cre female mice are similarly resistant to inflammatory bone loss in both ligature-induced periodontitis and K/BxN serum-transfer arthritis models. Bulk RNA-seq of mandibular-derived preosteoclasts from LSD1LysM-Cre mice with ligature-induced periodontitis revealed the upregulation of genes involved in inflammation, lipid metabolism, and immune response. Notably, LSD1 deletion blocked osteoclastogenesis even under TGF-β and TNF co-stimulation, which is an alternative RANKL-independent differentiation pathway. Upregulation of Nlrp3, Hif1α, and Acod1 in LSD1LysM-Cre preosteoclasts suggests that LSD1 is essential for repressing inflammatory and metabolic programs that otherwise hinder osteoclast commitment. These findings establish LSD1 as a critical epigenetic gatekeeper integrating inflammatory and metabolic signals to regulate osteoclast differentiation and bone resorption. Therapeutic inhibition of LSD1 may selectively mitigate inflammatory bone loss while preserving physiological bone remodeling. Full article

Rheumatoid arthritis (RA) is a progressive and systemic autoimmune disease, characterized by a chronic inflammatory process, affecting the lining of the synovial joints, many body organs/systems, and blood vessels. Its pathological hallmarks are hyperplasic synovium, bone erosion, and progressive joint destruction. Rheumatoid arthritis affects over 20 million people, with a worldwide prevalence of 0.5–1.0%, exhibiting gender, ethnic, and geographical differences. The progressive disability severely impairs physical motion and quality of life and is finally leading to a shortened life span. The pathogenesis of RA is a complex and still poorly understood process in which genetic and environmental factors are principally associated. Current treatment mostly relies on conventional/non-biological disease-modifying anti-rheumatic drugs (cDMARDs), analgesics, non-steroidal anti-inflammatory drugs, glucocorticoids, steroids, immunosuppresants, and biologic DMARDs, which only control inflammation and pain. Along with side effects (drug toxicity and intolerance), these anti-rheumatic drugs possess limited efficacy. Therefore, the discovery of novel multi-target therapeutics with an improved safety profile that function as inhibitors of RA-linked signaling systems are in high demand, and this is in the interest of both patients and clinicians. Plant-derived extracts, nutritional supplements, dietary medicine, and molecules with anti-inflammatory activity represent promising adjuvant agents or alternatives for RA therapeutics. This review not only aims to discuss the basic features of RA pathogenesis, risk factors, and signaling pathways but also highlights the research progress in pre-clinical RA in in vitro and in vivo models, revealing new avenues in the management of the disease in terms of comprehensive multidisciplinary strategies originating from medicinal plants and plant-derived molecules. Full article

Rheumatoid arthritis (RA) is one of the most representative autoimmune diseases. The peculiarity of this disease is synovial inflammation, which results in joint destruction and often disability. Although there are still several pathogenetic mechanisms to be clarified, lately, most studies have highlighted the involvement of mitochondria in the onset and progression of the disease. Mitochondrial functions are connected to many metabolic processes and the delivery of proinflammatory mediators. Mitochondria play a crucial role in the physiopathology of RA, contributing to chronic inflammation, cartilage and bone injury and chronic autoimmune response. Mitochondrial activity influences many aspects of the disease that will be discussed in terms of their correlation with the onset and persistence of RA, starting from mitochondrial dynamics up to bone homeostasis, passing through DAMPs and affecting immune cell functionality. Recent therapeutic approaches aim to improve mitochondrial function, reduce oxidative stress, modulate mitochondria-mediated inflammation and restore energy metabolism homeostasis. Full article

Tanshinones are a class of lipophilic diterpenoid quinones extracted from Salvia miltiorrhiza (Dan shen), a widely used herb in traditional Chinese medicine. These compounds, particularly tanshinone IIA (T-IIA) and sodium tanshinone sulfonate (STS), have been acknowledged for their broad spectrum of biological activities, including anti-inflammatory, antioxidant, anti-tumor, antiresorptive, and antimicrobial effects. Recent studies have highlighted the potential of tanshinones in the treatment of osteolytic diseases, characterized by excessive bone resorption, such as osteoporosis, rheumatoid arthritis, and periodontitis. The therapeutic effects of tanshinones in these diseases are primarily attributed to their ability to inhibit osteoclast differentiation and activity, suppress inflammatory cytokine production (e.g., tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6), and modulate critical signaling pathways, including NF-kB, MAPK, PI3K/Akt, and the RANKL/RANK/OPG axis. Additionally, tanshinones promote osteoblast differentiation and mineralization by enhancing the expression of osteogenic markers such as Runx2, ALP, and OCN. Preclinical models have demonstrated that T-IIA and STS can significantly reduce bone destruction and inflammatory cell infiltration in arthritic joints and periodontal tissues while also enhancing bone microarchitecture in osteoporotic conditions. This review aims to provide a comprehensive overview of the pharmacological actions of tanshinones in osteolytic diseases, summarizing current experimental findings, elucidating underlying molecular mechanisms, and discussing the challenges and future directions for their clinical application as novel therapeutic agents in bone-related disorders, especially periodontitis. Despite promising in vitro and in vivo findings, clinical evidence remains limited, and further investigations are necessary to validate the efficacy, safety, and pharmacokinetics of tanshinones in human populations. Full article

Open reduction and internal fixation (ORIF) is widely regarded as the primary treatment for acetabular fractures, but limitations arise in complex cases, leading to non-anatomical reductions and increased risk of post-traumatic osteoarthritis. Given the high incidence of secondary arthritis (12–57%) following ORIF, total hip arthroplasty (THA) is often necessitated, particularly in scenarios unsuitable for ORIF, such as extensive comminution or combined femoral head and neck fractures. The surgical landscape has shifted from a traditional “fix or replace” to a more integrated “fix and replace” approach, especially beneficial in managing elderly patients with osteoporotic bones. THA is applied across various timelines, including acute (0–3 weeks), delayed (3 weeks to 3 months), and late (beyond 3 months), each presenting distinct challenges and requiring specific strategies to optimize outcomes. The importance of precise bone defect classifications and the role of dual mobility cups in reducing dislocation risks are highlighted, alongside the use of modern surgical and fixation techniques to improve stability and patient outcomes. Enhanced recovery protocols and meticulous postoperative management are critical to addressing complications, such as infections and hardware interference, tailoring treatment approaches to each patient’s needs, and advancing care for complex acetabular fractures. Full article

Background/Objectives: Rheumatoid arthritis (RA) is a chronic inflammatory disease frequently accompanied by comorbid conditions that contribute to disability and worsen long-term outcomes. Among these, malnutrition and osteosarcopenia remain under-recognised. This cross-sectional study aimed to assess the prevalence of malnutrition and osteosarcopenia among elderly women with RA and explore the clinical impact of these conditions. Methods: Sixty-five women over 65 years with RA were evaluated using Global Leadership Initiative on Malnutrition (GLIM) criteria for malnutrition and EWGSOP2-based assessments for sarcopenia; bone status was measured by dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS), and three-dimensional DXA (3D-DXA). Results: Malnutrition was identified in 49.2% and osteosarcopenia in 52.3% of participants. A significant bidirectional association was observed: malnourished patients had higher rates of osteosarcopenia (65.6% vs. 34.4%; p < 0.05), and osteosarcopenic patients were more frequently malnourished (61.8% vs. 39.1%; p < 0.05). Both conditions were associated with older age, lower body mass index (BMI), impaired muscle parameters, and reduced bone mineral density. Malnourished and osteosarcopenic patients reported worse fatigue and lower physical quality of life, despite similar inflammatory activity. Significant correlations were found between muscle mass indices and bone quality metrics assessed by 3D-DXA. These findings highlight a substantial burden of malnutrition and osteosarcopenia in elderly women with RA, even with well-controlled disease despite similar inflammatory activity (mean Disease Activity Score 28: 2.8 ± 1.0; 43.1% in remission. Conclusions: There is a substantial burden of malnutrition and osteosarcopenia in elderly women with RA that support the integration of systematic nutritional and musculoskeletal screening into routine care. Future studies should evaluate age- and disease-specific mechanisms and assess the benefit of multidisciplinary strategies to prevent frailty and improve long-term outcomes. Full article

Background/Objectives: The most common limb-salvage procedure for end-stage ankle arthropathy with severe bone defect is arthrodesis. Successful fusion requires rigid metal fixation, effective filling of the bone defect space, and maximal securing of the contact area between the tibia and talus. In cases with severe bone defect, sufficient grafting using autogenous bone alone is limited, and there is still controversy regarding the effectiveness of allogeneic or xenogeneic bone grafting. This study aimed to evaluate the intermediate-term clinical outcomes after shortening arthrodesis using fibular osteotomy for ankle arthropathy with severe bone defect. Methods: Twenty-two patients with shortening ankle arthrodesis were followed up ≥ 3 years. All operations were performed by one senior surgeon and consisted of internal fixation with anterior fusion plate, fibular osteotomy, and autogenous bone grafting. The causes of ankle joint destruction were failed total ankle arthroplasty (7 cases), neglected ankle fracture (6 cases), delayed diagnosis of degenerative arthritis (5 cases), avascular necrosis of talus (2 cases), and diabetic neuroarthropathy (2 cases). Clinical outcomes including daily living and sport activities were evaluated with the Foot and Ankle Outcome Score (FAOS) and the Foot and Ankle Ability Measure (FAAM). Radiological evaluation included fusion rate, time to fusion, leg length discrepancy, and degenerative change in adjacent joints. Results: The FAOS and FAAM scores significantly improved from a mean of 21.8 and 23.5 points preoperatively to 82.2 and 83.4 points at final follow-up, respectively (p < 0.001). Visual analogue scale for pain during walking significantly improved from a mean of 7.7 points preoperatively to 1.4 points at final follow-up (p < 0.001). The average time to complete fusion was 16.2 weeks, and was achieved in all patients. The average difference in leg length compared to the contralateral side was 11.5 mm based on physical examination, and 13.8 mm based on radiological examination. During the average follow-up of 56.2 months, no additional surgery was required due to progression of degenerative arthritis in the adjacent joints, and no cases required the use of height-increasing insoles in daily life. Conclusions: Shortening ankle arthrodesis using fibular osteotomy and anterior fusion plate demonstrated satisfactory intermediate-term clinical outcomes and excellent fusion rate. Advantages of this procedure included rigid fixation, preservation of the subtalar joint, effective filling of the bone defect space, and maximal securing of the contact area for fusion. The leg length discrepancy, which was concerned to be a main shortage, resulted in no significant clinical symptoms or discomfort in most patients. Full article

Background/Objectives: Osteoarthritis is a degenerative joint disease that affects people worldwide. It is characterized by joint pain, synovial inflammation, and the degradation of articular cartilage with subchondral bone. Presently, there is no known cure, and pharmacological treatment options are limited. Blueberries contain phytochemicals, which have been linked to positive health benefits and may offer therapeutic benefits. Therefore, the purpose of this study was to examine the dose-dependent effects of whole blueberries on arthritis symptoms in a monosodium iodoacetate (MIA)-induced rat model of osteoarthritis. Methods: Forty female rats were used for this study. Thirty were injected with MIA to induce joint degradation associated with osteoarthritis. Ten served as controls without MIA induction. The MIA-induced rats were randomized into three groups. All groups were fed a casein-based diet, with two of the MIA-induced groups receiving an addition of whole-blueberry powder at 5% and 10%. Fasted blood specimens and tissues of interest were collected post-euthanasia for analysis. Mechanical allodynia and joint widths were assessed throughout this study. Results: MIA induction resulted in changes in pain behaviors and the development of mechanical allodynia. The MIA injection produced inflammation, pain symptoms, and behaviors that are representative of those observed in humans with osteoarthritis. The incorporation of whole blueberries into diets reduced pain behaviors and inflammation. Conclusions: Overall, whole blueberries showed limited, non-dose-dependent effects in the MIA-induced rat model of osteoarthritis. While some outcomes improved in blueberry-treated groups, the overall results were not consistently significant. These preliminary findings suggest potential biological activity and support the further investigation of blueberries’ therapeutic efficacy. Full article

Background and Objectives: Bisphosphonates (BP) like zoledronic acid (ZA) and alendronic acid (AA) are used for osteoporosis (OP) or other bone-related conditions as well as to prevent the spread of metastases and in rheumatoid arthritis treatment. However, they have been associated with an increased risk of osteonecrosis of the jaw (ONJ). This systematic review aimed to assess the incidence and risk of ONJ in osteoporotic patients treated with ZA or AA and evaluate the impact of treatment duration. Material and Methods: The systematic literature review was conducted following PRISMA guidelines. The keywords “Zoledronic acid,” “Alendronic acid,” “Osteoporosis,” and “Osteonecrosis” were searched in PubMed and ScienceDirect databases. Selection criteria included studies on humans written in English, published from 2014. The systematic review protocol was registered in the PROSPERO register under the following number: CRD42024587046. Results: A total of 7 studies with 98,717 osteoporotic patients met the criteria, showing a higher ONJ incidence with ZA than AA. Six studies linked longer BP use to increased ONJ risk, which quadrupled after 5 years of AA use. A positive correlation was found between BP use (≥3 years) and ONJ in OP patients, primarily affecting females over 60. ONJ appeared after 1 year with AA, increasing over time, while ZA-related ONJ emerged as early as 5 months with a higher overall incidence. Conclusions: ZA poses a higher ONJ risk and incidence and earlier onset than AA, occurring within 5 months versus 1 year for AA. These findings emphasize the need for careful monitoring, especially in long-term BP therapy with additional risk factors. Full article

Background: Myelotoxicity, usually manifested by moderate leukopenia (particularly neutropenia), is a well-known adverse drug reaction to azathioprine (AZA) therapy. Thiopurine methyltransferase (TMPT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) genotyping are not routinely performed in patients starting AZA therapy due to their low cost-effectiveness. Additionally, the concomitant use of xanthine oxidase inhibitors and 5-aminosalicylates may slow the metabolism of 6-mercaptopurine. Case Description: We describe a case of a 26-year-old Caucasian man with Crohn’s disease and psoriatic arthritis treated with mesalazine and AZA (100 mg daily) who developed prolonged bone marrow aplasia and neutropenic fever after increasing the daily dose of AZA from 100 to 150 mg (from 44 to 66 mg/m²), without frequent total blood count monitoring. Discontinuation of AZA, multiple transfusions of red blood cells and platelet concentrate, filgrastim, empirical antibiotic therapy, and antiviral and antifungal prophylaxis were obtained after 11 days complete recovery of bone marrow aplasia. Methods: Genomic DNA genotyping of coding regions of TPMT (exons 2–9) and NUDT15 (exons 1–3). Results: Heterozygous alleles in the untranslated region (c.460G>A and c.719A>G) associated with TPMT deficiency and a benign variant (c.*7G>A) in the 3′-UTR of NUDT15 with no effect on enzyme activity were found. Conclusions: This case highlights the importance of monitoring the total blood count frequently during the first weeks of treatment with moderate-to-high doses of AZA. Furthermore, the interaction between AZA and mesalazine may play a significant role in the development of prolonged bone marrow aplasia. Full article