Search Results (173)

Background/Objectives: Cannabinoid use is rising among patients undergoing spinal fusion, yet its influence on bone healing is poorly defined. The endocannabinoid system (ECS)—through cannabinoid receptors 1 (CB1) and 2 (CB2)—modulates skeletal metabolism. We reviewed preclinical, mechanistic and clinical evidence to clarify how individual cannabinoids affect fracture repair and spinal arthrodesis. Methods: PubMed, Web of Science and Scopus were searched from inception to 31 May 2025 with the terms “cannabinoid”, “CB1”, “CB2”, “spinal fusion”, “fracture”, “osteoblast” and “osteoclast”. Animal studies, in vitro experiments and clinical reports that reported bone outcomes were eligible. Results: CB2 signaling was uniformly osteogenic. CB2-knockout mice developed high-turnover osteoporosis, whereas CB2 agonists (HU-308, JWH-133, HU-433, JWH-015) restored trabecular volume, enhanced osteoblast activity and strengthened fracture callus. Cannabidiol (CBD), a non-psychoactive phytocannabinoid with CB2 bias, accelerated early posterolateral fusion in rats and reduced the RANKL/OPG ratio without compromising final union. In contrast, sustained or high-dose Δ⁹-tetrahydrocannabinol (THC) activation of CB1 slowed chondrocyte hypertrophy, decreased mesenchymal-stromal-cell mineralization and correlated clinically with 6–10% lower bone-mineral density and a 1.8–3.6-fold higher pseudarthrosis or revision risk. Short-course or low-dose THC appeared skeletal neutral. Responses varied with sex, age and genetic background; no prospective trials defined safe perioperative dosing thresholds. Conclusions: CB2 activation and CBD consistently favor bone repair, whereas chronic high-THC exposure poses a modifiable risk for nonunion in spine surgery. Prospective, receptor-specific trials stratified by THC/CBD ratio, patient sex and ECS genotype are needed to establish evidence-based cannabinoid use in spinal fusion. Full article

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

Xylosyltransferase-I (XT-I) plays a crucial role in skeletal development and cartilage integrity. An XT-I deficiency is linked to severe bone disorders, such as Desbuquois dysplasia type 2. While animal models have provided insights into XT-I’s role during skeletal development, its specific effects on adult bone homeostasis, particularly in human mesenchymal stem cell (hMSC) differentiation, remain unclear. This study investigates how XT-I deficiency impacts the differentiation of hMSCs into chondrocytes, osteoblasts, and adipocytes—key processes in bone formation and repair. The aim of this study was to elucidate for the first time the molecular mechanisms by which XT-I deficiency leads to impaired bone homeostasis. Using CRISPR-Cas9-mediated gene editing, we generated XYLT1 knockdown (KD) hMSCs to assess their differentiation potential. Our findings revealed significant disruption in the chondrogenic differentiation in KD hMSCs, characterized by the altered expression of regulatory factors and extracellular matrix components, suggesting premature chondrocyte hypertrophy. Despite the presence of perilipin-coated lipid droplets in the adipogenic pathway, the overall leptin mRNA and protein expression was reduced in KD hMSCs, indicating a compromised lipid metabolism. Conversely, osteogenic differentiation was largely unaffected, with KD and wild-type hMSCs exhibiting comparable mineralization processes, indicating that critical aspects of osteogenesis were preserved despite the XYLT1 deficiency. In summary, these results underscore XT-I’s pivotal role in regulating differentiation pathways within the bone marrow niche, influencing cellular functions critical for skeletal health. A deeper insight into bone biology may pave the way for the development of innovative therapeutic approaches to improve bone health and treat skeletal disorders. Full article

Meniscal degradation is considered a driver of osteoarthritis (OA) progression, but the underlying mechanisms leading to age-related meniscus degeneration remain unknown. This study aimed to identify key genes and pathways involved in meniscal degradation through a computational analysis. Gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database. Differential expression gene (DEG) analysis was performed using DESeq2 accompanied by functional enrichment analysis, protein–protein interaction (PPI) and clustering analysis. Additionally, gene set enrichment analysis (GSEA) was performed. A total of 85 mRNAs (DEMs) and 8 long non-coding RNAs (DE LncRNAs) were found to be differentially expressed in OA meniscus tissues. Among 85 DEMs, 12 genes were found to be known OA-related genes, whereas 15 genes acted as transcription regulators, including RUNX2 and TBX4, which were identified as effector genes for OA. Enrichment analysis revealed the implication of DEMs in cartilage-degradation-related processes, including inflammatory pathways, lipid metabolism, extracellular matrix organization and superoxide/nitric oxide metabolic processes. Target genes of DE lncRNAs were found to be involved in chondrocyte differentiation and pathways related to cartilage degradation. A comparative analysis of meniscus, synovium and cartilage datasets identified three genes (GJB2, PAQR5 and CLEC12A) as being differentially expressed across all three OA-affected tissues, which were implicated in inflammatory and cholesterol metabolism processes. Our results support that shared mechanisms lead to meniscal and cartilage degradation during OA progression, providing further insights into the processes underlying OA pathogenesis and potential therapeutic targets for knee OA. Full article

Osteoarthritis (OA) is a leading cause of disability worldwide and is characterized by the gradual degradation of articular cartilage in weight-bearing joints, notably the knees and hips. However, the primary morphological and anatomical determinants of the disease onset and progression remain unclear. This narrative overview examines how variations in cartilage thickness—traditionally viewed as a biomechanical protective feature—can paradoxically compromise metabolic homeostasis during prolonged sedentary behavior. Intriguingly, compelling evidence suggests that despite its superior load-bearing capacity, thicker cartilage faces greater challenges in solute transport, a limitation further exacerbated by the formation of diffusion-resistant boundary layers at the cartilage–fluid interface during immobilization. This phenomenon restricts nutrient influx and impedes waste clearance, leading to the accumulation of catabolic byproducts in deep cartilage zones and accelerated extracellular matrix breakdown, potentially influencing OA pathogenesis. By critically synthesizing current debates on mechanical loading with emerging data on metabolic dysregulation, particularly nutrient diffusion limitations, this analysis underscores the urgent need for targeted investigation of synovial–cartilage interface dynamics and chondrocyte metabolism under low-motion conditions. This study further advocates for strategic research focusing on often-overlooked, silent metabolic imbalances among sedentary populations and recommends early-intervention strategies, such as periodic joint mobilization, ergonomic adaptations, and public-health campaigns, to reduce prolonged sitting, preserve joint function, and guide more effective prevention and management approaches for non-traumatic OA in contemporary contexts. Full article

Background/Objectives: Lumbar disc herniation (LDH) is the most common condition associated with low back pain, and it adversely impacts individuals’ health. The interplay between energy metabolism and apoptosis is critical, as the loss of viable cells in the intervertebral disc (IVD) can lead to a cascade of degenerative changes. Efferocytosis is a key biological process that maintains homeostasis by removing apoptotic cells, resolving inflammation, and promoting tissue repair. Therefore, enhancing mitochondrial energy metabolism and efferocytosis function in IVD cells holds great promise as a potential therapeutic approach for LDH. Methods: In this study, energy metabolism and efferocytosis-related differentially expressed genes (EMERDEGs) were identified from the transcriptomic datasets of LDH. Machine learning approaches were used to identify key genes. Functional enrichment analyses were performed to elucidate the biological roles of these genes. The functions of the hub genes were validated by RT-qPCR. The CIBERSORT algorithm was used to compare immune infiltration between LDH and Control groups. Additionally, we used single-cell RNA sequencing dataset to analyze cell-specific expression of the hub genes. Results: By using bioinformatics methods, we identified six EMERDEGs hub genes (IL6R, TNF, MAPK13, ELANE, PLAUR, ABCA1) and verified them using RT-qPCR. Functional enrichment analysis revealed that these genes were primarily associated with inflammatory response, chemokine production, and cellular energy metabolism. Further, we identified candidate drugs as potential treatments for LDH. Additionally, in immune infiltration analysis, the abundance of activated dendritic cells, neutrophils, and gamma delta T cells varied significantly between the LDH group and Control group. The scRNA-seq analysis showed that these hub genes were mainly expressed in chondrocyte-like cells. Conclusions: The identified EMERDEG hub genes and pathways offer novel insights into the molecular mechanisms underlying LDH and suggest potential therapeutic targets. Full article

Sclerostin (SOST) is a specific osteocyte protein. During the differentiation and proliferation of osteoblasts and osteoclasts, the high expression of SOST can inhibit bone formation and contribute to osteoporosis and the bone metastasis of malignant tumors. Most of the research on SOST has focused on bone cells, but studies have found that SOST is not a specific product of bone cells but that it is also expressed by articular chondrocytes. SOST can regulate the progression of osteoarthritis in bone and cartilage, promote subchondral bone sclerosis, and inhibit cartilage degeneration. A review of the literature found that SOST can not only regulate bone metabolism, but it is also expressed in cardiovascular, kidney, liver, and other tissues, influencing the occurrence and development of diseases in these organs and tissues. Studies have found that diseases of extra-bone organs, such as atherosclerosis, aneurysm, chronic kidney disease, and cirrhosis, may be related to the expression of SOST. Simultaneously, long-term exercise can reduce SOST levels, especially in areas of high bone strain. Prolonged exercise induces bone adaptation to mechanical stress, resulting in diminished responsiveness of bone cells to exercise and a reduction in serum SOST levels. Short-term acute exercise can elevate serum SOST levels, but these results are often limited by age, gender, and energy status. In general, serum SOST rises immediately after short-term acute exercise, returning to baseline or even decreasing after exercise. Full article

Mechanical stress is known to be a pivotal risk factor in the development of OA. However, the involvement of repetitive compressive loading in mitochondrial dysfunction in chondrocytes remains unclear. The aim of this study was to investigate whether physiologic levels of repetitive mechanical force affect the regulation of energy metabolism and activities of mitochondrial function regulators, sirtuin 1 and nicotinamide adenine dinucleotide (NAD) in chondrocytes, and to clarify any correlation with chondrocyte catabolic activity. Repetitive physiological mechanical stress was applied in a 3D chondrocyte-collagen scaffold construct, and the 3D cultured tissues were collected at different time points by collagenase treatment to collect cellular proteins. Changes in chondrocyte activity (cell proliferation, MMP-13 production), energy metabolism regulator levels (sirtuin 1), mitochondrial function (ATP production, NAD level), and the expression level of the osteogenic and hypertrophic chondrogenic transcription factor, runt-related transcription factor 2 (Runx2), were measured. Treatment with repetitive compressive loading resulted in no significant change in the cell viability of chondrocytes. In the repetitive mechanical loading group, there were statistically significant increases in MMP-13 production and expression of both sirtuin 1 and Runx2 in chondrocytes relative to the non-loading control group. Furthermore, ATP production and NAD activity in mitochondria decreased in the repetitive mechanical loading group. Our present study reveals that in chondrocytes, repetitive compressive loading accelerated sirtuin activation, which requires and consumes NAD within mitochondria, leading to a decrease of NAD and ultimately in reduced mitochondrial ATP production. Additionally, since sirtuin 1 is known to positively regulate Runx2 activity in chondrocytes, the activation of sirtuin 1 by repetitive load stimulation may induce an increase in the expression of Runx2, which promotes the expression of MMP-13, and subsequently enhances MMP-13 production. Our findings indicate that repetitive compression loading-mediated mitochondrial dysfunction plays a pivotal role in the progression of OA, primarily by driving the downregulation of ATP production and promoting the expression of the matrix-degrading enzyme MMP-13. Full article

Osteoarthritis (OA) is a long-term degenerative condition of the joints, characterized by persistent inflammation, progressive cartilage breakdown, and impaired mitochondrial function. Recent studies have shown that hyperactivation of the mTORC1 pathway and metabolic reprogramming of chondrocytes contribute to disease progression. Nitazoxanide (NTZ), an oral antiparasitic agent approved by the Food and Drug Administration, has shown anti-inflammatory and mitochondrial protective effects in various disease situations; despite this, its application in osteoarthritis has yet to be fully investigated. Here, we assessed the therapeutic efficacy of NTZ using IL-1β-stimulated primary chondrocytes derived from patients with OA. NTZ substantially reduced the expression of proinflammatory cytokines and matrix metalloproteinases, restored mitochondrial membrane potential, and reduced mitochondrial reactive oxygen species levels. NTZ also effectively reversed IL-1β-induced glycolytic metabolic changes by inhibiting glucose uptake and GLUT1 expression. Mechanistically, NTZ inhibited the activation of the mTORC1 pathway and substantially increased AMPK phosphorylation. The siRNA-mediated AMPK knockdown negated NTZ-induced mitochondrial and metabolic improvements, suggesting that AMPK is a key upstream regulator of the protective actions of NTZ. NTZ can, therefore, effectively inhibit inflammatory metabolic reprogramming and mitochondrial dysfunction in OA chondrocytes through AMPK-dependent mTORC1 signaling inhibition, highlighting its potential as a disease-modifying therapy for OA. Full article

Background/Objectives: Growth in childhood and adolescence is influenced by a complex interaction of genetic, environmental, and hormonal factors, with growth hormone (GH) and insulin-like growth factor 1 (IGF-1) playing crucial roles in linear growth and development. However, chronic inflammation, often detected in situations like inflammatory bowel disease and juvenile idiopathic arthritis, can significantly disrupt the GH/IGF-1 axis, causing a relevant growth impairment. Methods: We conducted a retrospective review focusing on the role of cytokines in the GH-IGF-1 axis and growth. Results: Inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 have been shown to contribute to GH resistance through an array of mechanisms that involve the downregulation of GH receptors and alterations in IGF-1 metabolism. This disruption negatively impacts the growth plate, particularly by impairing chondrocyte proliferation and differentiation, which are essential for proper bone elongation. This review delves into the intricate relationship among growth, chronic inflammation, and GH-IGF-1 axis, emphasizing the contribution of inflammatory cytokines in modulating GH signaling. It also highlights how cytokines can interfere with the molecular pathways that regulate skeletal growth, ultimately leading to growth disturbances in children suffering from chronic inflammatory diseases. Conclusions: The findings underscore the importance of controlling inflammation in affected individuals to mitigate its detrimental effects on growth and ensure that children may reach their growth full potential. Full article

Background: Denosumab, a receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitor, demonstrates therapeutic effects beyond traditional osteoporosis management through the RANK/RANKL/osteoprotegerin pathway. Methods: This narrative review analyzed 37 studies (2018–2024) examining denosumab’s broader physiological effects and clinical applications. Results: Long-term safety data spanning 10 years showed sustained fracture prevention efficacy with a favorable benefit/risk profile. Compared to bisphosphonates, denosumab demonstrated superior outcomes in bone mineral density improvement and fracture risk reduction, particularly in elderly and frail populations. It enhanced muscular function by improving appendicular lean mass and grip strength while reducing fall risk. The drug showed potential cardiovascular benefits through its effects on cardiac and smooth muscle function. Notably, denosumab use was associated with reduced Type II diabetes mellitus risk through improved glucose metabolism. Additionally, it demonstrated promise in osteoarthritis treatment by suppressing osteoclast activity and chondrocyte apoptosis. While there are multisystem benefits, vigilance is required regarding adverse events, including hypocalcemia, infection risk, cutaneous reactions, and osteonecrosis of the jaw. Conclusions: Denosumab exhibits potential benefits in bone and systemic metabolism. Further research is needed to fully understand its therapeutic potential beyond osteoporosis and optimize clinical applications across different populations. Full article

Osteoarthritis (OA) is a chronic and debilitating joint disease characterized by progressive cartilage degeneration for which no definitive cure exists. Conventional management approaches often rely on fragmented and poorly coordinated pharmacological and non-pharmacological interventions that are inconsistently applied throughout the disease course. Persistent controversies regarding the clinical efficacy of chondroprotective agents, frequently highlighted by pharmacovigilance agencies, underscore the need for a structured evidence-based approach. Emerging evidence suggests that synchronizing pharmacotherapy and exercise regimens with circadian biology may optimize therapeutic outcomes by addressing early pathological processes, including low-grade inflammation, oxidative stress, and matrix degradation. Recognizing the influence of the chondrocyte clock on these processes, this study proposes a ‘prototype’ for a novel framework that leverages the circadian rhythm-aligned administration of traditional chondroprotective agents along with tailored, accessible exercise protocols to mitigate cartilage breakdown and support joint function. In addition, this model-based framework emphasizes the interdependence between cartilage chronobiology and time-of-day-dependent responses to exercise, where strategically timed joint activity enhances nutrient and waste exchange, mitigates mitochondrial dysfunction, supports cellular metabolism, and promotes tissue maintenance, whereas nighttime rest promotes cartilage rehydration and repair. This time-sensitive, comprehensive approach aims to slow OA progression, reduce structural damage, and delay invasive procedures, particularly in weight-bearing joints such as the knee and hip. However, significant challenges remain, including inter-individual variability in circadian rhythms, a lack of reliable biomarkers for pharmacotherapeutic monitoring, and limited clinical evidence supporting chronoexercise protocols. Future large-scale, longitudinal trials are critical to evaluate the efficacy and scalability of this rational integrative strategy, paving the way for a new era in OA management. Full article

Cilia are highly specialized cellular projections emanating from the cell surface, whose defects contribute to a spectrum of diseases collectively known as ciliopathies. Intraflagellar transport protein 88 (IFT88) is a crucial component of the intraflagellar transport-B (IFT-B) subcomplex, a protein complex integral to ciliary transport. The absence of IFT88 disrupts the formation of ciliary structures; thus, animal models with IFT88 mutations, including the oak ridge polycystic kidney (ORPK) mouse model and IFT88 conditional allelic mouse model, are frequently employed in molecular and clinical studies of ciliary functions and ciliopathies. IFT88 plays a pivotal role in a variety of cilium-related processes, including organ fibrosis and cyst formation, metabolic regulation, chondrocyte development, and neurological functions. Moreover, IFT88 also exhibits cilium-independent functions, such as spindle orientation, planar cell polarity establishment, and actin organization. A deeper understanding of the biological events and molecular mechanisms mediated by IFT88 is anticipated to advance the development of diagnostic and therapeutic strategies for related diseases. Full article

Ear reconstruction surgeries for congenital deformities and trauma are common, highlighting the need for improved cartilage regeneration. Lactoferrin (LF), a natural and cost-effective protein, is promising due to its anti-inflammatory, antimicrobial, and prochondrogenic properties. This study investigates the effects of LF on the viability, proliferation, and chondrogenesis of rabbit auricular chondrocytes. For in vitro studies, auricular chondrocytes were cultured for three passages, after which 3D pellets were formed. LF significantly increased chondrocyte metabolic activity by 1.5 times at doses of 10 and 500 μg/mL. At passage 3, LF at concentrations of 10 and 100 μg/mL increased cell proliferation rates by 2- and 1.5-fold, respectively. Immunohistochemical staining of the pellets demonstrated that LF at 10 μg/mL increased the amount of sex-determining region Y-Box Transcription Factor 9 (Sox9)+ cells by 30%, while at 100 μg/mL, it doubled the type II collagen deposits. For in vivo studies, a rabbit ear defect model was utilized. On post-operative day 60, the LF-treated group exhibited more mature cartilage regeneration, with a higher density of elastic fibers. By day 90 post-surgery, LF application led to the restoration of normal elastic cartilage throughout the defect. These findings suggest that LF promotes auricular chondrocytes chondrogenesis and could be beneficial for tissue engineering of the elastic cartilage. Full article

Intra-articular corticosteroids, such as triamcinolone acetonide (TA), help reduce pain related to osteoarthritis (OA), but they may impair cartilage metabolism. In contrast, platelet-rich plasma (PRP) therapy, a regenerative therapy, has shown potential to promote healing and regeneration of articular cartilage. This study investigates the effects of combining PRP with TA to treat osteoarthritis in racehorses. The study proposes that PRP injection following TA treatment could reduce side effects and improve treatment outcomes. Firstly, in the in vitro study, chondrocytes were exposed to different TA concentrations, with or without PRP. TA dramatically reduced chondrocyte viability. However, this was prevented by the addition of PRP, which also increased cell proliferation. In the in vivo study, 32 racehorses with metacarpophalangeal (MCP) joint OA were separated into two groups: one received only TA, while the other received TA followed by PRP. For both groups, there were improved flexion assessments one week following the last treatment, but by two weeks following the last treatment, only TA+PRP had improved flexion assessments. TA+PRP also had improved lameness scores two weeks after the last treatment. In conclusion, combining PRP with TA could enhance chondrocyte viability and provide a better long-term therapeutic option for treating OA in racehorses. Further trials are required to thoroughly assess this technique’s safety and efficacy. Full article