Biomedicines

Research

Jump to: Review

11 pages, 664 KB

Open AccessArticle

Validation of the Neutrophil–Lymphocyte Ratio as a Mortality Risk Stratification Marker in Patients with Proximal Femoral Fractures

by Alessandro Civinini, Filippo Leggieri, Marta Massenzi, Christian Carulli, Roberto Civinini and Matteo Innocenti

Biomedicines 2026, 14(3), 551; https://doi.org/10.3390/biomedicines14030551 - 27 Feb 2026

Viewed by 726

Abstract

Background/Objectives: Proximal femoral fractures (PFF) are associated with substantial morbidity and mortality in elderly patients. Early identification of individuals at increased risk of death remains challenging. The neutrophil-to-lymphocyte ratio (NLR) is an inexpensive and readily available biomarker reflecting systemic inflammation and physiological stress, [...] Read more.

Background/Objectives: Proximal femoral fractures (PFF) are associated with substantial morbidity and mortality in elderly patients. Early identification of individuals at increased risk of death remains challenging. The neutrophil-to-lymphocyte ratio (NLR) is an inexpensive and readily available biomarker reflecting systemic inflammation and physiological stress, but its role as a risk stratification tool in surgically treated PFF patients is not fully established. The aim of this study was to validate NLR as a prognostic biomarker for mortality risk stratification in elderly hip fracture patients by evaluating its independent association with mortality, establishing clinically relevant risk categories, and assessing its ability to identify distinct mortality risk groups. Methods: This retrospective cohort study included 1113 patients aged ≥ 65 years who underwent surgery for AO/OTA 31.A (trochanteric) or 31.B (femoral neck) proximal femoral fractures between January 2021 and February 2024 at a single institution. NLR was calculated from routine admission bloodwork. The primary outcome was all-cause mortality. Kaplan–Meier survival analysis stratified patients by clinically relevant NLR categories (<5, 5–10, >10). Cox proportional hazards regression identified independent predictors of mortality. ROC analysis was performed secondarily to identify an optimal binary threshold. Results: At mean follow-up of 33.9 months, overall mortality was 36.2% (352/972). Stratified survival analysis demonstrated a clear dose–response relationship, with mortality rates of 26.2%, 36.5%, and 54.4% for NLR < 5, 5–10, and >10, respectively (log-rank p < 0.001). In multivariable Cox regression, NLR remained independently associated with mortality (HR = 1.042, 95% CI: 1.032–1.053, p < 0.001) after adjusting for age and time to surgery. ROC analysis identified an optimal binary cut-off of 6.59 (AUC 0.614). Conclusions: Elevated preoperative NLR is independently associated with increased mortality following surgery for proximal femoral fractures, particularly in very elderly patients. Given its simplicity and universal availability, NLR may represent a useful adjunct for early perioperative risk stratification. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition)

► Show Figures

Figure 1

17 pages, 411 KB

Open AccessArticle

Exercise-Associated Changes in Body Composition and Metabolic Biomarkers Following an Eight-Week Submaximal Exercise Program in Women Across Different BMI Categories and with Type 2 Diabetes

by Kıvanç Buru, Vedat Çınar, Taner Akbulut, Mehdi Aslan, Meva Ceren Orgun, Fidan Çınar, Orhan Uluçay and Do-Youn Lee

Biomedicines 2026, 14(2), 473; https://doi.org/10.3390/biomedicines14020473 - 21 Feb 2026

Viewed by 907

Abstract

Background/Objectives: This study evaluated exercise-induced changes in body composition and metabolic biomarkers in women across distinct BMI categories and individuals with Type 2 diabetes. Methods: In this quasi-experimental study, 40 sedentary women were stratified into five groups (n = 8): [...] Read more.

Background/Objectives: This study evaluated exercise-induced changes in body composition and metabolic biomarkers in women across distinct BMI categories and individuals with Type 2 diabetes. Methods: In this quasi-experimental study, 40 sedentary women were stratified into five groups (n = 8): underweight, normal weight, overweight, obese, and T2DM. The rigorous eight-week supervised program utilized submaximal exercise at 70–85% heart rate reserve, calculated via the Karvonen method and monitored by telemetry. Assessments included anthropometric parameters (BMI, fat mass, visceral fat) and serum biomarkers (irisin, myonectin, HIF-1α, insulin, glucose). Fasting venous samples were collected at baseline and 72 h post-intervention to minimize acute effects, then analyzed using validated ELISA protocols. Statistical data were evaluated using parametric or non-parametric tests with significance set at p < 0.05. Results: Post-intervention, significant reductions in weight, fat mass, and visceral fat occurred in overweight, obese, and T2DM groups (p < 0.05). Muscle mass increased across all cohorts. Fasting insulin and glucose decreased significantly in all except the underweight group, with the most pronounced improvements in T2DM and obese participants. Serum irisin increased significantly across all groups (p < 0.05), indicating a universal exercise-induced myokine response. Conversely, myonectin levels decreased significantly only in the normal-weight group, while HIF-1α increased specifically in the T2DM cohort. These findings suggest that baseline BMI and metabolic status are critical determinants of exercise responsiveness, leading to heterogeneous biomarker patterns despite consistent improvements in body composition and basic glycemic regulation. Conclusions: An eight-week submaximal program effectively improves body composition and glycemic regulation, though specific biomarker responses are highly dependent on baseline BMI and metabolic status. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition)

► Show Figures

Figure 1

24 pages, 16307 KB

Open AccessArticle

A Novel Concept of Tissue Micro-Instability as the Underlying Mechanism of Osteophytosis in Human Knee Osteoarthritis

by Alexey Volkov, Vera Lyalina, Gulnara Eshmotova, Natalia Serejnikova, Sofia Petrova, George Airapetov, Evgeniya Parshina, Anton Zalygin, Ekaterina Belitskaya, Vladimir Oleinikov, Anton Bonartsev, Svetlana Borisovskaya, Nikolai Zagorodny and Alexey Prizov

Biomedicines 2026, 14(2), 283; https://doi.org/10.3390/biomedicines14020283 - 27 Jan 2026

Cited by 1 | Viewed by 1148

Abstract

Osteophytes (OPs) are a diagnostic hallmark of osteoarthritis (OA). However, the mechanisms underlying their initiation and their relationship with early subchondral bone changes remain poorly understood. Existing research primarily relies on animal models and late-stage OA tissue, leaving the initial morphological events leading [...] Read more.

Osteophytes (OPs) are a diagnostic hallmark of osteoarthritis (OA). However, the mechanisms underlying their initiation and their relationship with early subchondral bone changes remain poorly understood. Existing research primarily relies on animal models and late-stage OA tissue, leaving the initial morphological events leading to OP formation unclear. Background/Objectives: This study aimed to identify early changes in the subchondral bone as a key trigger for OP initiation in human OA through a comprehensive histological analysis of the subchondral area, including its peripheral regions. Methods: We conducted an extensive histological examination of full-section human tibial plateaus, including load-bearing and non-load-bearing compartments, obtained from patients with early and late stages of OA. Results: Our data demonstrate that subchondral bone changes, including osteoporosis, osteosclerosis, and microcracks, begin at the pre-chondropathic stage alongside microscopically intact cartilage. We identified a previously undescribed zone on the vertical wall of the tibial condyle (the VEPLS zone), characterized by reduced calcium content in the cortical plate and the persistence of embryonic cartilage, making it morphologically vulnerable. The first event in OP formation is microcracks in the cortical angle and the adjacent subchondral trabecula. These injuries initiate reparative osteogenesis, which, under continuous traumatic load (presumably shear forces due to joint instability), becomes insufficient, leading to cortical angle protrusion and OP formation. OP growth is accompanied by the deformation of the VEPLS zone cortical plate, causing vascular impairment and exacerbating bone weakness. Conclusions: Based on our findings, we propose the concept of tissue micro-instability. This concept posits that osteophytosis results from chronic microcracks and failed bone regeneration in vulnerable subchondral structures, induced by joint instability. We define an OP as a pathological outgrowth arising from this tissue micro-instability. Our study highlights the critical role of the peripheral subchondral area, particularly the VEPLS zone, in OA pathogenesis. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition)

► Show Figures

Figure 1

13 pages, 739 KB

Open AccessArticle

The Role of Posturography in the Diagnosis of Temporomandibular Disorders and Their Impact on Body Posture

by Krzysztof Antczak, Waldemar Pluta, Michał Lubkowski, Aleksandra Radecka and Anna Lubkowska

Biomedicines 2025, 13(12), 2857; https://doi.org/10.3390/biomedicines13122857 - 24 Nov 2025

Cited by 2 | Viewed by 1119

Abstract

Background: Posturography is a diagnostic method used to evaluate postural stability by recording body sway and the distribution of pressure on the ground. Temporomandibular disorders (TMDs) involve musculoskeletal and neuromuscular dysfunctions affecting the temporomandibular joint, masticatory muscles, and associated structures. Given the [...] Read more.

Background: Posturography is a diagnostic method used to evaluate postural stability by recording body sway and the distribution of pressure on the ground. Temporomandibular disorders (TMDs) involve musculoskeletal and neuromuscular dysfunctions affecting the temporomandibular joint, masticatory muscles, and associated structures. Given the anatomical and functional connections between the stomatognathic system and postural control mechanisms, this study aimed to assess whether TMDs influence body posture and balance as measured by posturographic parameters. Methods: 75 volunteers, aged 19–48, were included. The TMD group (n = 45) was diagnosed based on the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), and the control group (n = 30) showed no signs of TMD. All participants underwent posturographic assessment and jaw opening range measurement. Posturography was performed using a pressure platform that recorded the center of pressure (COP) in static conditions. Postural stability was assessed using the Romberg test with eyes open and closed. Results: No statistically significant differences were found between the TMD and control groups in COP parameters, including ellipse area (EA) and total load distribution. Within both groups, COP sway increased significantly in the eyes-closed (EC) condition, as reflected by a greater unsteadiness length (UL). In contrast, EA was larger in the eyes-open (EO) condition in both groups, indicating a wider but more controlled spatial dispersion of COP. Intra-group analysis further revealed a significantly higher load on the left side in the control group only. Conclusions: The results do not support a significant postural imbalance in individuals with TMD compared to healthy controls. However, increased sway with eyes closed suggests that visual input plays a key role in postural control, regardless of TMD status. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition)

► Show Figures

Figure 1

22 pages, 8067 KB

Open AccessArticle

Exercise and Carnosine Modulate Microbiota-Derived Metabolites, Myokines, and Cardiometabolic Profiles in Rats: A Randomized Controlled Trial

by Kenan Bozbay, Vedat Çınar, Taner Akbulut, Yavuz Yasul, Mehmet Hanifi Yalçın, Meva Ceren Orgun, Süleyman Aydın and Do-Youn Lee

Biomedicines 2025, 13(12), 2853; https://doi.org/10.3390/biomedicines13122853 - 22 Nov 2025

Viewed by 1247

Abstract

Background/Objectives: Carnosine and exercise independently improve metabolic health, yet their combined effects on myokines and microbiota-derived metabolites remain underexplored. This study evaluated the synergistic impact of carnosine supplementation and exercise intensity on microbiota-derived metabolites, as well as skeletal muscle and myocardial expression [...] Read more.

Background/Objectives: Carnosine and exercise independently improve metabolic health, yet their combined effects on myokines and microbiota-derived metabolites remain underexplored. This study evaluated the synergistic impact of carnosine supplementation and exercise intensity on microbiota-derived metabolites, as well as skeletal muscle and myocardial expression of irisin and myonectin, focusing on lipid and glycemic regulation. Methods: A randomized post-test control study was conducted using 49 male Sprague Dawley rats (9 weeks old; 250.39 ± 1.85 g), divided into 7 groups: control (C), sham (S), moderate-intensity continuous training (MICT), high-intensity continuous training (HICT), carnosine (CA), MICT with carnosine (MICT_CA), and HICT with carnosine (HICT_CA). Interventions included treadmill-based moderate or high-intensity training and carnosine supplementation (100 mg/kg/day) for 5 weeks. Blood samples were collected post-decapitation; plasma was analyzed for lipid profile, glycemic parameters, and microbiota-derived metabolites using enzymatic and ELISA methods. Irisin and myonectin levels were assessed in plasma and myocardial and skeletal muscle tissues via ELISA and immunohistochemistry. Results: The HICT_CA group showed the lowest body weight, highest HDL-C, and lowest LDL-C, TC, TG, and atherogenic index. Irisin and myonectin levels in skeletal muscle and myocardium were also highest in HICT_CA. The trimethylamine N-oxide (TMAO) was lowest and S-equol highest in HICT_CA, whereas indoxyl sulfate (IS) peaked in HICT and was lowest in the C group. Principal component analysis revealed strong positive associations between HICT_CA and cardiometabolic biomarkers. Conclusions: High-intensity training combined with carnosine may reduce weight gain, improve lipid and glycemic profiles, and enhance myokines and microbiota-derived metabolites. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition)

► Show Figures

Graphical abstract

12 pages, 1178 KB

Open AccessArticle

DAC^®_, a Hyaluronan Derivative in the Form of a Gel, Is Effective in Preventing Periprosthetic Joint Infection During Arthroplasty Revision in Patients with Comorbidities: A Retrospective, Observational, 1:1-Matched Case–Control Clinical Investigation

by Giuseppe Ricciardi, Giancarlo Giuliani, Arminio Armando, Raffaele Quitadamo, Rosario Demita and Costantino Stigliani

Biomedicines 2025, 13(10), 2408; https://doi.org/10.3390/biomedicines13102408 - 30 Sep 2025

Viewed by 1125

Abstract

Background/Objectives: Joint arthroplasty revision and comorbidities are considered two increased risk factors for periprosthetic joint infection (PJI), a complication that may lead to prolonged hospital stay, continued antibiotic therapy, and serious consequences, including amputation and, in extreme cases, death of the patient. [...] Read more.

Background/Objectives: Joint arthroplasty revision and comorbidities are considered two increased risk factors for periprosthetic joint infection (PJI), a complication that may lead to prolonged hospital stay, continued antibiotic therapy, and serious consequences, including amputation and, in extreme cases, death of the patient. DAC^® is an absorbable barrier in the form of a gel that, when applied as a coating, protects implants from bacterial colonization. The aim of this case–control study was to explore whether the device could decrease the risk of PJI in a cohort of patients who underwent arthroplasty revision and were affected by comorbidities. Methods: We carried out a retrospective 1:1-matched case–control investigation in 96 patients who underwent arthroplasty revision between January 2023 and December 2024; these patients had at least 6 months of follow-up, had comorbidities, and were treated with DAC^® gel. The control group consisted of 96 subjects who received standard of care. Demographics, comorbidities, type of arthroplasty, adverse event onset, and incidence of PJI were recorded for all patients. Results: No significant differences in relevant demographics, type of arthroplasty revision, or number or type of comorbidities, except for smoking, were observed between the two groups. At 6-month follow-up, no PJIs were recorded in the DAC^® treatment group, whereas five (5.2%) PJIs were observed in the control group (p = 0.0235). No adverse event or impairment of implant osseointegration related to the use of DAC^® was observed. Conclusions: The DAC^® bioabsorbable hydrogel acts as a physical barrier when applied over an arthroplasty revision implant, protecting it from bacterial adhesion and preventing biofilm formation. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition)

► Show Figures

Figure 1

13 pages, 829 KB

Open AccessArticle

Can We Successfully Discontinue Anti-Tumor Necrosis Factor-α Treatment in Children with Non-Systemic Juvenile Idiopathic Arthritis? The Experience of a Tertiary Center

by Ekaterina I. Alexeeva, Irina T. Tsulukiya, Tatyana M. Dvoryakovskaya, Dmitry A. Kudlay, Ivan A. Kriulin, Maria S. Botova, Natalya M. Kondratyeva, Elizaveta A. Krekhova, Meiri Sh. Shingarova, Maria Y. Kokina, Anna N. Fetisova, Kseniya B. Isaeva, Aleksandra M. Chomakhidze, Christina V. Chibisova and Mikhail M. Kostik

Biomedicines 2025, 13(10), 2329; https://doi.org/10.3390/biomedicines13102329 - 24 Sep 2025

Cited by 1 | Viewed by 1097

Abstract

Background: Some patients with juvenile idiopathic arthritis (JIA) can successfully undergo withdrawal of treatment with anti-tumor necrosis factor alpha (anti-TNF-α) therapy, which may reduce economic and treatment-related burdens and the potential morbidity of treatment for at least 6 months. Currently, no guidelines exist [...] Read more.

Background: Some patients with juvenile idiopathic arthritis (JIA) can successfully undergo withdrawal of treatment with anti-tumor necrosis factor alpha (anti-TNF-α) therapy, which may reduce economic and treatment-related burdens and the potential morbidity of treatment for at least 6 months. Currently, no guidelines exist on the appropriate withdrawal of anti-TNF-α therapy once clinically inactive disease (CID) has been achieved. This study aimed to assess the possibility of withdrawing anti-TNF-α therapy in children with non-systemic JIA after achieving long-term clinical remission. Methods: This single-center retrospective cohort study included data from 137 non-systemic JIA patients treated with anti-TNF-α therapy (etanercept or adalimumab) and having maintained CID for at least 24 months during treatment. Demographic, laboratory, and treatment data were collected at JIA onset, at the initiation of anti-TNF-α therapy, every 6 months during therapy, and at the time of disease flare. Anti-TNF-α therapy was discontinued abruptly after discussing it with the patients and their families in each case. Outcomes were assessed using standard criteria for remission in JIA (ACRpedi and Wallace criteria). Results: Following withdrawal of TNF-α inhibitors, 93/137 patients (67.9%) experienced a disease flare, with a median time to flare of 7 months (3; 14). Thirty-two percent of patients remained in remission for a median of 63 months. Absence of flare during the first 22 months after discontinuation was associated with prolonged biologic-free remission (odds ratio 682; 95% CI 38.6–12,062; p < 0.0001), with 83% sensitivity and 100% specificity (area under the ROC curve 0.967). Most flares involved arthritis (76%) and/or uveitis (24%), primarily affecting knees, ankles, and wrists. Inflammatory markers were generally lower at flare compared to baseline. Biological therapy was resumed in 84/93 patients (90.3%), achieving at least a 50% improvement according to ACRpedi criteria within 3 months and remission according to Wallace criteria within 6 months. Conclusion: Over two-thirds of patients with non-systemic JIA who achieve CID experience a flare within seven months of anti-TNF-α discontinuation. Re-initiation of biologic therapy is effective in restoring remission. These results indicate that prolonged biologic-free remission is possible in a subset of patients, highlighting the need for individualized withdrawal strategies and careful post-discontinuation monitoring. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition)

► Show Figures

Graphical abstract

18 pages, 2994 KB

Open AccessArticle

Altered Expression of Cell Cycle Regulators and Factors Released by Aged Cells in Skeletal Muscle of Patients with Bone Fragility: A Pilot Study on the Potential Role of SIRT1 in Muscle Atrophy

by Angela Falvino, Roberto Bonanni, Beatrice Gasperini, Ida Cariati, Angela Chiavoghilefu, Amarildo Smakaj, Virginia Veronica Visconti, Annalisa Botta, Riccardo Iundusi, Elena Gasbarra, Virginia Tancredi and Umberto Tarantino

Biomedicines 2025, 13(6), 1350; https://doi.org/10.3390/biomedicines13061350 - 31 May 2025

Cited by 2 | Viewed by 2107

Abstract

Background/Objectives: Cellular aging represents a crucial element in the progression of musculoskeletal diseases, contributing to muscle atrophy, functional decline, and alterations in bone turnover, which promote fragility fractures. However, knowledge about expression patterns of factors potentially involved in aging and senescence at [...] Read more.

Background/Objectives: Cellular aging represents a crucial element in the progression of musculoskeletal diseases, contributing to muscle atrophy, functional decline, and alterations in bone turnover, which promote fragility fractures. However, knowledge about expression patterns of factors potentially involved in aging and senescence at the tissue level remains limited. Our pilot study aimed to characterize the expression profile of cell cycle regulators, factors released by aged cells, and sirtuin 1 (SIRT1) in the muscle tissue of 26 elderly patients undergoing hip arthroplasty, including 13 with low-energy fracture and 13 with osteoarthritis (OA). Methods: The mRNA expression levels of cyclin-dependent kinase inhibitor 1A (CDKN1A), cyclin-dependent kinase inhibitor 1B (CDKN1B), cyclin-dependent kinase inhibitor 2A (CDKN2A), p53, tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-15 (IL-15), chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 3 (CCL3), growth differentiation factor 15 (GDF15), and SIRT1 were evaluated in muscle tissue by qRT-PCR. In addition, immunohistochemistry and Western blotting analysis were conducted to measure the protein levels of SIRT1. Results: A marked muscle atrophy was observed in fractured patients compared to the OA group, in association with an up-regulation of cell cycle regulators and factors released by the aged cells. The expression of matrix metallopeptidase 3 (MMP3), plasminogen activator inhibitor 1 (PAI-1), and fas cell surface death receptor (FAS) was also investigated, although no significant differences were observed between the two experimental groups. Notably, SIRT1 expression was significantly higher in OA patients, confirming its role in maintaining muscle health during aging. Conclusions: Further studies will be needed to clarify the role of SIRT1 in the senescence characteristic of age-related musculoskeletal disorders, counteracting the muscle atrophy that predisposes to fragility fractures. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition)

► Show Figures

Figure 1

Review

Jump to: Research

18 pages, 1711 KB

Open AccessReview

Moringa as a Functional Food for Rheumatoid Arthritis: A Scoping Review of Evidence

by Hiba Murtadha Al-Saadi, Sophia Ogechi Ekeuku, Jasmine Jia Thung Wong, Nurul Nabihah Zahanordin, Norliza Muhammad and Kok-Yong Chin

Biomedicines 2026, 14(3), 565; https://doi.org/10.3390/biomedicines14030565 - 1 Mar 2026

Viewed by 4063

Abstract

Background/Objectives: Rheumatoid arthritis is a chronic autoimmune disease characterised by persistent synovitis and joint destruction. While conventional pharmacotherapies, such as disease-modifying anti-rheumatic drugs, are effective, they are often limited by significant adverse effects and high costs. Moringa, a medicinal plant rich in [...] Read more.

Background/Objectives: Rheumatoid arthritis is a chronic autoimmune disease characterised by persistent synovitis and joint destruction. While conventional pharmacotherapies, such as disease-modifying anti-rheumatic drugs, are effective, they are often limited by significant adverse effects and high costs. Moringa, a medicinal plant rich in bioactive compounds, has emerged as a potential functional food adjunct for managing this condition. This scoping review systematically maps the evidence regarding the efficacy of moringa supplementation in alleviating the pathology of rheumatoid arthritis. Methods: A comprehensive search of PubMed, Scopus, and Web of Science was performed using a standardised search string to identify original articles investigating the effects of moringa on models of or patients with rheumatoid arthritis. Results: A total of 19 eligible studies, comprising in vitro models, preclinical animal studies, and human clinical trials, were included. Phytochemical profiling revealed the presence of potent anti-inflammatory and antioxidant constituents, including flavonoids and isothiocyanates, in various plant parts. Preclinical findings demonstrated that moringa extracts significantly inhibited paw oedema, pannus formation, and cartilage erosion by downregulating proinflammatory cytokines (tumour necrosis factor-alpha, interleukin-1 beta, and interleukin-6) and suppressing nuclear factor kappa B signalling. Clinical trials corroborated these benefits, showing that moringa leaf extracts were associated with reduced disease activity scores and systemic inflammatory markers in patients. Additionally, moringa supplementation alleviated depression associated with rheumatoid arthritis, suggesting a dual therapeutic impact. Conclusions: The current evidence supports moringa as a promising functional food adjunct, though further standardised trials are warranted to establish optimal dosing and clinical guidelines. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition)

► Show Figures

Figure 1

20 pages, 983 KB

Open AccessReview

In Vivo Models of Diabetes: Unravelling Molecular Pathways in Metabolic and Skeletal Complications

by Haryati Ahmad Hairi, Nor Hidayah Mustafa, Ahmad Nazrun Shuid and Muhammad Zulfiqah Sadikan

Biomedicines 2026, 14(1), 243; https://doi.org/10.3390/biomedicines14010243 - 21 Jan 2026

Cited by 4 | Viewed by 1214

Abstract

Background/Objectives: Diabetic osteoporosis (DOP) is a metabolic bone disorder marked by reduced bone mass, impaired microarchitecture and elevated fracture risk arising from type 1 and type 2 diabetes. Understanding its pathophysiology is essential for developing effective interventions. Method: A broad literature [...] Read more.

Background/Objectives: Diabetic osteoporosis (DOP) is a metabolic bone disorder marked by reduced bone mass, impaired microarchitecture and elevated fracture risk arising from type 1 and type 2 diabetes. Understanding its pathophysiology is essential for developing effective interventions. Method: A broad literature search of Scopus and PubMed (2015–2025) using diabetic osteoporosis-related keywords identified relevant English in vivo studies, which were screened, extracted, and narratively summarised for this review. Results: In vivo models, including high-fat-diet (HFD), streptozotocin (STZ) and combined HFD + STZ protocols, are widely used to investigate DOP mechanisms. HFD models mimic obesity-induced insulin resistance, chronic hyperglycaemia and low-grade inflammation, leading to suppressed osteoblast activity, enhanced osteoclastogenesis and accumulation of advanced glycation end products (AGEs). Ultimately, they compromise bone microarchitecture and mechanical strength. STZ models replicate type 1 diabetes by inducing β-cell destruction, insulin deficiency, oxidative stress, osteoblast apoptosis and inflammatory pathways promoting bone resorption. The combined HFD + STZ model integrates insulin resistance and partial β-cell dysfunction, closely reflecting type 2 diabetes pathology, including trabecular bone loss, collagen glycation and disrupted osteoblast–osteoclast signalling. Mechanistically, DOP involves impaired insulin/IGF-I signalling, AGE–RAGE interactions, oxidative stress and inflammation, resulting in diminished bone formation and quality. These models provide robust platforms for exploring molecular mechanisms and evaluating potential therapies, including Wnt pathway modulators, antioxidants and ferroptosis inhibitors. Conclusions: Collectively, preclinical in vivo models are indispensable for understanding DOP pathophysiology and developing strategies to mitigate diabetic bone fragility. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition)

► Show Figures

Figure 1

23 pages, 1032 KB

Open AccessReview

Effects of Cannabidiol on Bone Health: A Comprehensive Scoping Review

by Shabbir Adnan Shakir and Kok-Yong Chin

Biomedicines 2026, 14(1), 208; https://doi.org/10.3390/biomedicines14010208 - 18 Jan 2026

Viewed by 2183

Abstract

Background/objectives: Cannabidiol (CBD) is a non-psychoactive constituent of Cannabis sativa, which has potential skeletal benefits through modulation of bone cell function and inflammatory signalling. However, evidence of its effects and mechanisms in bone health remains fragmented. This scoping review summarised the current [...] Read more.

Background/objectives: Cannabidiol (CBD) is a non-psychoactive constituent of Cannabis sativa, which has potential skeletal benefits through modulation of bone cell function and inflammatory signalling. However, evidence of its effects and mechanisms in bone health remains fragmented. This scoping review summarised the current findings on the impact of CBD on bone outcomes and its mechanisms of action. Methods: A systematic search of PubMed, Scopus, and Web of Science was conducted in October 2025 for original studies published in English, with the primary objective of examining the effects of CBD on bone health, regardless of study design. After applying inclusion and exclusion criteria, 24 primary studies were included. Data on model design, CBD formulation, treatment parameters, bone-related outcomes, and proposed mechanisms were extracted and analysed descriptively. Results: Among the studies included, eleven demonstrated beneficial effects of CBD on bone formation, mineralisation, callus quality, or strength; eleven showed mixed outcomes; and two demonstrated no apparent benefit. Previous studies have shown that CBD suppresses bone resorption by reducing osteoclast differentiation and activity while promoting osteoblast proliferation and matrix deposition. Mechanistically, CBD’s effects involve activation of cannabinoid receptor 2, modulation of the receptor activator of nuclear factor-κB ligand/osteoprotegerin pathway, and regulation of osteoblastogenic and osteoclastogenic signalling through bone morphogenetic protein, Wnt, mitogen-activated protein kinase, nuclear factor-κB, and peroxisome proliferator-activated receptor signalling. The anti-inflammatory and antioxidant actions of CBD further contribute to a favourable bone microenvironment. Conclusions: Preclinical evidence suggests that CBD has a bone-protective role through multifaceted pathways that enhance osteoblast function and suppress osteoclast activity. Nevertheless, robust human trials are necessary to confirm its efficacy, determine its optimal dosing, and clarify its long-term safety. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition)

► Show Figures

Graphical abstract

38 pages, 3048 KB

Open AccessReview

Mitochondria as a Disease-Relevant Organelle in Rheumatoid Arthritis: A Key Breakout in Fight Against the Disease

by Antonella Iaconis, Francesco Molinari, Roberta Fusco and Rosanna Di Paola

Biomedicines 2025, 13(7), 1708; https://doi.org/10.3390/biomedicines13071708 - 13 Jul 2025

Cited by 5 | Viewed by 3907

Abstract

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 [...] Read more.

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

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition)

► Show Figures

Graphical abstract

33 pages, 1902 KB

Open AccessReview

Sending the Signal to Bone: How Tumor-Derived EVs Orchestrate Pre-Metastatic Niche Formation and Skeletal Colonization

by Alhomam Dabaliz, Hagar Mahmoud, Raffi AlMutawa and Khalid S. Mohammad

Biomedicines 2025, 13(7), 1640; https://doi.org/10.3390/biomedicines13071640 - 4 Jul 2025

Cited by 7 | Viewed by 3129

Abstract

Bone is a preferred site for disseminated tumor cells, yet the molecular mechanisms that prepare the skeletal microenvironment for metastatic colonization are only beginning to be understood. At the heart of this process are extracellular vesicles (EVs), nano-sized, lipid-encapsulated particles secreted by cancer [...] Read more.

Bone is a preferred site for disseminated tumor cells, yet the molecular mechanisms that prepare the skeletal microenvironment for metastatic colonization are only beginning to be understood. At the heart of this process are extracellular vesicles (EVs), nano-sized, lipid-encapsulated particles secreted by cancer cells and stromal components. This review consolidates current findings that position EVs as key architects of the bone-metastatic niche. We detail the biogenesis of EVs and their organotropic distribution, focusing on how integrin patterns and bone-specific ligands guide vesicle homing to mineralized tissues. We then outline the sequential establishment of the pre-metastatic niche, driven by EV-mediated processes including fibronectin deposition, stromal cell reprogramming, angiogenesis, neurogenesis, metabolic reconfiguration, and immune modulation, specifically, the expansion of myeloid-derived suppressor cells and impaired lymphocyte function. Within the bone microenvironment, tumor-derived EVs carrying microRNAs and proteins shift the balance toward osteoclastogenesis, inhibit osteoblast differentiation, and disrupt osteocyte signaling. These alterations promote osteolytic destruction or aberrant bone formation depending on tumor type. We also highlight cutting-edge imaging modalities and single-EV omics technologies that resolve EV heterogeneity and identify potential biomarkers detectable in plasma and urine. Finally, we explore therapeutic approaches targeting EVs, such as inhibition of nSMase2 or Rab27A, extracorporeal EV clearance, and delivery of engineered, bone-targeted vesicles, while addressing translational challenges and regulatory considerations. This review offers a roadmap for leveraging EV biology in predicting, preventing, and treating skeletal metastases by integrating advances across basic biology, bioengineering, and translational science. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Musculoskeletal Diseases: From Molecular Basis to Therapy—3rd Edition

Share This Special Issue

Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Related Special Issues

Published Papers (13 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI