HMB (Anti-catabolic)

Temporomandibular disorders (TMDs) occur frequently within the general population and are the most common non-dental cause of orofacial pain. Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative joint disease (DJD). There have been several different methods of treatment of TMJ OA listed, including pharmacotherapy among others. Due to its anti-aging, antioxidative, bacteriostatic, anti-inflammatory, immuno-stimulating, pro-anabolic and anti-catabolic properties, oral glucosamine seems to be a potentially very effective agent in the treatment of TMJ OA. The aim of this review was to critically assess the efficacy of oral glucosamine in the treatment of TMJ OA on the basis of the literature. PubMed and Scopus databases were analyzed with the keywords: (temporomandibular joints) AND ((disorders) OR (osteoarthritis)) AND (treatment) AND (glucosamine). After the screening of 50 results, eight studies have been included in this review. Oral glucosamine is one of the symptomatic slow-acting drugs for osteoarthritis. There is not enough scientific evidence to unambiguously confirm the clinical effectiveness of glucosamine supplements in the treatment of TMJ OA on the basis of the literature. The most important aspect affecting the clinical efficacy of oral glucosamine in the treatment of TMJ OA was the total administration time. Administration of oral glucosamine for a longer period of time, i.e., 3 months, led to a significant reduction in TMJ pain and a significant increase in maximum mouth opening. It also resulted in long-term anti-inflammatory effects within the TMJs. Further long-term, randomized, double-blind studies, with a unified methodology, ought to be performed to draw the general recommendations for the use of oral glucosamine in the treatment of TMJ OA.

OBJECTIVES: The aim of this first global systematic review on selected nutraceuticals was to synthesize and evaluate scientific relevant data available in the literature. Evidences that can support health, physiological or functional benefit on osteoarthritis (OA) were gathered and the level of evidence relative to each of these ingredients was highlighted. METHODOLOGY: Relevant scientific data (positive or not) regarding OA were searched for five groups of compounds (avocado/soybean unsaponifiables (ASU), n-3 polyunsaturated fatty acids, collagen hydrosylates (CHs), vitamin D, polyphenols) within preclinical (in vitro and in vivo), epidemiological, and clinical studies. The following criteria were evaluated to assess the methodology quality of each study: (1) study question; (2) study population; (3) primary endpoint; (4) study design (randomization, control, blinding, duration of follow up); (5) data analysis and interpretation. A scientific consensus was determined for all studied nutraceuticals to evaluate their efficacy in OA. RESULTS: The studied compounds demonstrated different potencies in preclinical studies. Most of them have demonstrated anti-catabolic and anti-inflammatory effects by various inhibitory activities on different mediators. Vitamin D showed a pro-catabolic effect in vitro and the polyphenol, Genistein, had only anti-inflammatory potency. The evaluation of the clinical data showed that ASU was the only one of the studied ingredients to present a good evidence of efficacy, but the efficient formulation was considered as a drug in some countries. Pycnogenol showed moderate evidence of efficacy, and vitamin D and collagen hydrolysate demonstrated a suggestive evidence of efficacy, whereas curcumin, epigallocatechin-3-gallate (EGCG) and resveratrol had only preclinical evidence of efficacy due to the lack of clinical data. The literature gathered for n-3 PUFA, nobiletin and genistein was insufficient to conclude for their efficacy in OA. CONCLUSION: Additional data are needed for most of the studied nutraceuticals. Studies of good quality are needed to draw solid conclusions regarding their efficacy but nutraceuticals could represent good alt

OBJECTIVE: To review the pharmacological properties and the available clinical data of full length parathyroid hormone (PTH) in post-menopausal osteoporosis. SOURCES: A MEDLINE search was completed, together with a review of information obtained from the manufacturer and from the medicine regulatory agencies. STUDY AND DATA SELECTION: Studies were selected according to relevance and availability. Relevant information (design, objectives, patients' characteristics, outcomes, adverse events, dosing, etc) was analyzed. RESULTS: Different studies have shown that, when administered intermittently as a subcutaneous injection in the abdomen, PTH increases bone mineral density (BMD) and prevents vertebral fractures. On completion of PTH therapy (up to 24 months), there is evidence that sequential treatment with alendronate is associated with a therapeutic benefit in terms of increase in BMD. Further trials are necessary to determine long-term safety and the role of PTH in combination with other treatments for osteoporosis and the effect of repeated cycles of PTH followed by an anti-catabolic agent. There are currently no completed comparative trials with other osteoporosis treatments. CONCLUSIONS: Full length PTH, given intermittently as an abdominal subcutaneous injection, appears to be a safe and efficacious treatment option for high risk osteoporosis. More data are needed to determine its specific role in osteoporosis treatment.

OBJECTIVE: To evaluate the efficacy and safety of the anti-catabolic ADAMTS-5 inhibitor S201086/GLPG1972 for the treatment of symptomatic knee osteoarthritis. DESIGN: ROCCELLA (NCT03595618) was a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 trial in adults (aged 40-75 years) with knee osteoarthritis. Participants had moderate-to-severe pain in the target knee, Kellgren-Lawrence grade 2 or 3 and Osteoarthritis Research Society International joint space narrowing (grade 1 or 2). Participants were randomized 1:1:1:1 to once-daily oral S201086/GLPG1972 75, 150 or 300 mg, or placebo for 52 weeks. The primary endpoint was change from baseline to week 52 in central medial femorotibial compartment (cMFTC) cartilage thickness assessed quantitatively by magnetic resonance imaging. Secondary endpoints included change from baseline to week 52 in radiographic joint space width, Western Ontario and McMaster Universities Osteoarthritis Index total and subscores, and pain (visual analogue scale). Treatment-emergent adverse events (TEAEs) were also recorded. RESULTS: Overall, 932 participants were enrolled. No significant differences in cMFTC cartilage loss were observed between placebo and S201086/GLPG1972 therapeutic groups: placebo vs 75 mg, P = 0.165; vs 150 mg, P = 0.939; vs 300 mg, P = 0.682. No significant differences in any of the secondary endpoints were observed between placebo and treatment groups. Similar proportions of participants across treatment groups experienced TEAEs. CONCLUSIONS: Despite enrolment of participants who experienced substantial cartilage loss over 52 weeks, during the same time period, S201086/GLPG1972 did not significantly reduce rates of cartilage loss or modify symptoms in adults with symptomatic knee osteoarthritis.

INTRODUCTION: The hyper-catabolic state is a devastating pathophysiological response to severe injury, infection or burns. Nandrolone decanoate (ND) is a potent anabolic steroid have many clinical indications, but not investigated in burn injuries yet. PATIENTS AND METHODS: A prospective randomized control study included 40 burned patients who were treated in Burn unit from burn injuries ranged from 20 to 40%. Both groups are objectively assessed, clinically and laboratory during treatment period till full recovery from burns' injury. Recall assessment of the drug safety after many years is achieved. RESULTS: ND showed highly significant results supporting its use in combating catabolic insults in burns patient. Both clinical findings and laboratory findings are correlated and highly support the use of ND in burns as new effective and safe long-lasting indication. CONCLUSION: This study results showed preservation of lean body mass and protein partition, as well as the near normal nitrogen balance in burn patients. Study proposes that nandrolone decanoate could be used in safe and effective way to combat hypercatabolic impact in burn injury.

OBJECTIVE: Inflammatory disease is catabolic and associated with insulin resistance, increased energy expenditure, lipolysis and muscle protein loss. The main contributors to these metabolic adaptations are inflammation, malnutrition and immobilisation. Controlled experimental models incorporating these central elements of hospitalisation are lacking. The aim of this study was to validate such a human experimental model. METHODS: In a randomized crossover design, six healthy young men underwent; (i) overnight fast (CTR), or (ii) exposure to systemic lipopolysaccharide (1 ng/kg) combined with 36-hour fast and bed rest (CAT). The difference in insulin sensitivity between CAT and CTR was the main outcome, determined by a hyperinsulinemic euglycemic glucose clamp. Palmitate, glucose, urea, phenylalanine and tyrosine tracers were infused to estimate metabolic shifts during interventions. Indirect calorimetry was used to estimate energy expenditure and substrate oxidation. RESULTS: Insulin sensitivity was 41% lower in CAT than in CTR (M-value, mg/kg/min): 4.3 ± 0.2 vs 7.3 ± 1.3, p<0.05. The median (min max) palmitate flux (μmol/min) was higher during CAT than in CTR (257.0 (161.7 365.4) vs 131.6 (92.3 189.4), p = 0.004), and protein kinetics did not differ between interventions. C-reactive peptide (mg/L) was elevated in CAT compared with CTR (30.57 ± 4.08 vs 1.03 ± 0.19, p<0.001). Energy expenditure increased by 6% during CAT compared with CTR (1869 ± 94 vs 1756 ± 58, p = 0.04), CAT having higher lipid oxidation rates (p = 0.01) and lower glucose oxidation rates (p = 0.03). Lipopolysaccharide caused varying abdominal discomfort 2 hours post-injection, which had disappeared the following day. CONCLUSION: We found that combined systemic inflammation, fasting and bed rest induced marked insulin resistance and increased energy expenditure and lipolysis, rendering this controlled experimental model suitable for anti-catabolic intervention studies, mimicking clinical conditions.

Studies in mice have suggested that osteocalcin plays an important role in glucose and fat metabolism. Since anti-resorptive drugs reduce circulating levels of osteocalcin they might be associated with increased fat mass and an increased risk of diabetes. Positive changes in body weight have been found in trials of alendronate and denosumab, but no significant effect in a previous trial of zoledronate. Whether those weight differences were in fat or lean mass is unknown. There were no effects of anti-resorptive treatments on fasting glucose concentrations or incidence of diabetes in those three studies. We have used our recent trial comparing zoledronate and placebo over 6 years in 2000 older osteopenic women to re-examine these questions. Both treatment groups lost body weight during the study (placebo 1.65 kg, zoledronate 1.05 kg), and this was significantly greater in the placebo group (P = 0.01). Both groups lost lean mass, and this loss was marginally (0.17 kg) but significantly (P = 0.02) greater in those receiving zoledronate. The placebo group had a mean loss of fat mass of 0.63 kg but there was no change in fat mass in the zoledronate group (between-groups comparison, P = 0.007). In the placebo group, there were 20 new diagnoses of diabetes, and in the zoledronate group, 19 (P = 0.87). Zoledronate prevented age-related loss of fat mass in these late postmenopausal women. The present study is the first to document a significant effect of zoledronate treatment on body weight, confirming results previously found with alendronate and denosumab. It also demonstrates that this is principally an effect to maintain fat mass rather than influencing lean mass, raising an important physiological question as to how anti-resorptive drugs have this effect on intermediary metabolism. It is possible that this anti-catabolic action contributes to the beneficial effects of anti-resorptive drugs on bone and longevity.

BACKGROUND & AIMS: Surgical stress provokes protein catabolism and hyperglycaemia that is enhanced in patients with type 2 diabetes (T2DM), and increases perioperative morbidity. This study hypothesized that perioperative administration of high dose intravenous (IV) amino acids (AA) will augment protein balance in T2DM patients receiving tight plasma glucose control via continuous IV insulin compared to standard plasma glucose control via subcutaneous (SC) insulin sliding scale. METHODS: Eighteen patients with well-controlled T2DM (HbA1C% < 7.1) undergoing colorectal surgery were assigned randomly to receive standard glucose control (6-10 mmol/l, SC insulin, n = 9) or tight glucose control (4-6 mmol/l, IV insulin, n = 9). Both groups received general anaesthesia and epidural analgesia. AA (1 ml/kg h Aminoven™ 10%, ∼2.4 g/kg d) were infused via a peripheral vein for two 3-h periods: at the beginning of surgery and in the post-operative care unit. Whole-body protein and glucose kinetics were assessed by stable isotope tracers, L-[1-13C]leucine and [6,6-2H2]glucose. RESULTS: Whole-body protein balance was positive after surgery in all patients. Since protein synthesis, breakdown and leucine oxidation were comparable in both groups, whole body protein balance was not different (p = 0.605). Tight glucose control suppressed endogenous glucose production (EGP, p < 0.001) and increased glucose clearance (p < 0.001) compared to standard glucose control during both study periods. No episode of hypoglycaemia occurred in either group. CONCLUSION: High-dose perioperative AA administration under optimal anti-catabolic care with epidural analgesia was effective in achieving a positive protein balance in T2DM patients undergoing surgery that was independent of glycaemic control strategy. Continuous IV insulin maintained normoglycaemia by inhibiting EGP and increasing glucose clearance. Improved glucose control, without a pronounced increase in protein balance with the intravenous insulin regimen, suggests perioperative protein metabolism may be less sensitive to insulin than is glucose.

BACKGROUND: Cystic fibrosis (CF) is a chronic catabolic disease often requiring hospitalization for acute episodes of worsening pulmonary exacerbations. Limited data suggest that vitamin D may have beneficial clinical effects, but the impact of vitamin D on systemic metabolism in this setting is unknown. OBJECTIVE: We used high-resolution metabolomics (HRM) to assess the impact of baseline vitamin D status and high-dose vitamin D3 administration on systemic metabolism in adults with CF with an acute pulmonary exacerbation. DESIGN: Twenty-five hospitalized adults with CF were enrolled in a randomized trial of high-dose vitamin D3 (250,000IU vitamin D3 bolus) versus placebo. Age-matched healthy subjects served as a reference group for baseline comparisons. Plasma was analyzed with liquid chromatography/ultra-high resolution mass spectrometry. Using recent HRM bioinformatics and metabolic pathway enrichment methods, we examined associations with baseline vitamin D status (sufficient vs. deficient per serum 25-hydroxyvitamin D concentrations) and the 7-day response to vitamin D3 supplementation. RESULTS: Several amino acids and lipid metabolites differed between CF and healthy control subjects, indicative of an overall catabolic state. In CF subjects, 343 metabolites differed (P<0.05) by baseline vitamin D status and were enriched within 7 metabolic pathways including fatty acid, amino acid, and carbohydrate metabolism. A total of 316 metabolites, which showed enrichment for 15 metabolic pathways-predominantly representing amino acid pathways-differed between the vitamin D3- and placebo-treated CF subjects over time (P<0.05). In the placebo group, several tricarboxylic acid cycle intermediates increased while several amino acid-related metabolites decreased; in contrast, little change in these metabolites occurred with vitamin D3 treatment. CONCLUSIONS: Numerous metabolic pathways detected by HRM varied in association with vitamin D status and high-dose vitamin D3 supplementation in adults with CF experiencing a pulmonary exacerbation. Overall, these pilot data suggest an anti-catabolic effect of high-dose vitamin D3 in this clinical setting.

Patients with advanced chronic heart failure (CHF) are characterized by progressive muscle wasting. The two E3-ligases Rnf28 and Atrogin-1 controlling the activation of the ubiquitinproteasome system might be of importance for the regulation of muscle size. Given the convincing effect of regular physical exercise training (ET) in CHF, it was the aim of the present trial to elucidate, whether ET affects both mentioned enzymes in CHF and whether this is associated with an increase in skeletal muscle mass. METHODS: 37 patients with severe CHF were randomized to 12 weeks of ET or sedentary lifestyle (control). The expression of Rnf28 and Atrogin-1 in the skeletal muscle was analyzed by RT-PCR and Western blotting. Skeletal muscle cross sectional area (CSA) was measured by computed tomography. RESULTS: In CHF patients ET led to a significant reduction in skeletal muscle mRNA transcription (from 14.3 ± 2.0 to 8.7 ± 1.4 arbitrary units; p<0.05 versus baseline and versus control for the change) and protein expression of Rnf28 (from 4.70 ± 1.35 to 2.84 ± 0.65 arbitrary units; p<0.05 versus baseline and versus control for the change). This was accompanied by a significant increase in total muscle CSA of both thighs (from 139.9 ± 5.2 to 149.2 ± 5.9 cm(2); p<0.05 versus baseline and versus control for the change). On the contrary, Atrogin-1 was not affected. CONCLUSION: In patients with advanced CHF, regular physical exercise training led to a decrease in Rnf28 expression in the skeletal muscle. This was linked to an increase in skeletal muscle cross sectional area, supporting the notion that ET has anti-catabolic properties in CHF.

A randomized trial was undertaken to evaluate the effects of postoperative indomethacin (IDM) administration on protein metabolism in 20 patients who underwent an uncomplicated distal gastrectomy and were placed on post-operative total parenteral nutrition (TPN). Ten patients (the IDM group) received 50 mg of IDM every 8 h after operation up to postoperative day (POD) 4 while the other ten patients (the control group) received neither IDM nor any other non-steroidal anti-inflammatory drug, postoperatively. Though the requirement for postoperative plasma transfusion was significantly greater in the IDM group, the albumin level on POD 1 was significantly lower in this group than in the control group. The postoperative changes of C-reactive protein, retinol binding protein, and pre-albumin between the two groups showed no difference. Moreover, the urinary 3-methylhistidine excretion, N-balance, and plasma aminogram on POD 4 also demonstrated no difference. We thus concluded that post-operative IDM administration after elective surgery has no additional anti-catabolic effect on the presence of TPN.

OBJECTIVE: Focal damage to articular cartilage incurred during joint injuries frequently progresses to post-traumatic osteoarthritis (PTOA) due to the limited intrinsic repair capacity of cartilage. Chondrogenic progenitor cells (CPCs) residing within the cartilage can contribute to repair if effectively recruited and activated. Early interventions that enhance CPC homing and their subsequent chondrogenesis offer a regenerative strategy to prevent PTOA progression, addressing the current lack of effective early clinical therapies. GDF5 stands out as a key protein involved in cartilage development, yet its potential to mobilize CPC-mediated regeneration remains underexplored. METHODS: We evaluated the effects of GDF5 on CPC migration, proliferation, chondrogenic differentiation, and anti-catabolic activity using in vitro CPC models. To assess CPC chemotaxis in a clinically relevant biomaterial context, GDF5 was incorporated into a hyaluronic acid/fibrin interpenetrating network (IPN) hydrogel and tested in an ex vivo cartilage defect model. RESULTS: GDF5 acted as a potent chemoattractant for CPCs, promoting their recruitment toward cartilage defects when delivered via a hyaluronic acid/fibrin IPN hydrogel in an ex vivo model. GDF5 also enhanced CPC proliferation, consistent with activation of a glycolysis-associated transcriptional program. In addition, GDF5 significantly upregulated chondrogenic markers, including SOX9, COL2a1, and ACAN, and elevated extracellular matrix components in CPCs, potentially through activation of the PI3K/AKT signaling pathway. Furthermore, GDF5 reduced expression of a key catabolic enzyme ADAMTS5, possibly through the WWP2/miR-140 axis. CONCLUSION: These findings highlight the versatile role of GDF5 on endogenous CPCs. When combined with a hydrogel platform, GDF5 may serve as an early therapeutic strategy to convert injured cartilage from a passive site of degeneration into one of active regeneration. © 2026. The Author(s).

Bone's ability to adapt to mechanical demands is governed by mechanoregulation, the process by which cells sense and respond to mechanical stimuli to maintain skeletal integrity. In osteoporosis, increased bone resorption activity leads to structural deterioration and elevated fracture risk. While existing pharmacological therapies aim to restore bone mass to reduce fracture risk, it is unclear how they modulate mechanoregulation, especially when combined with physical interventions. Here, we investigate the joint effects of load-bearing physical and pharmacological treatment in a female mouse model of osteoporosis using longitudinal in vivo micro-computed tomography and computational mechanics. We demonstrate that mechanical loading additively and synergistically enhanced predicted strength, bone volume, and mechanoregulation parameters when combined with anabolic therapies (parathyroid hormone and sclerostin antibody) but not with anti-catabolic treatments (bisphosphonates). Increases in predicted strength are associated with reductions in bone resorption rates, shifts in the (re)modeling thresholds as anticipated by Frost in the mechanostat theory, and the modeling capacity of anabolic pharmacological treatments. These findings underscore the therapeutic potential of combining anabolic pharmacological therapies with load-bearing physical activity, particularly in early treatment phases, to optimize bone adaptation and fracture prevention in osteoporosis management. © 2026. The Author(s).

Osteoarthritis (OA) lacks effective disease-modifying therapies. Nav1.7 has recently been identified as a regulator of both chondrocyte metabolism and pain, establishing it as a dual-acting therapeutic target in OA. This study evaluated lacosamide (LCM) as a disease-modifying candidate and developed a cartilage-targeted delivery strategy to enhance its translational potential. Sodium channel inhibitors (carbamazepine, oxcarbazepine, and LCM) were evaluated in primary human OA chondrocytes, cartilage explants, and a murine DMM model with systemic or intra-articular administration. Pain behavior was assessed by von Frey and open-field testing. A collagen II-based thermoresponsive hydrogel was developed for sustained intra-articular delivery, and outcomes were assessed by histology, immunohistochemistry, ELISA, and gene expression analyses. LCM was the most potent inhibitor in suppressing IL-1β-induced catabolism and promoting anabolism in human chondrocytes, showing greater efficacy at lower concentrations than carbamazepine or oxcarbazepine. Systemic LCM reduced cartilage degeneration and pain in murine OA and outperformed carbamazepine at equivalent doses, while intra-articular administration achieved superior protection and analgesia at one-tenth the dose. Mechanistically, LCM increased HSP70 and midkine secretion to drive anabolic and anti-catabolic responses. Sustained delivery via a collagen II-based hydrogel prolonged joint retention and enhanced therapeutic durability. Together with its clinical efficacy in Nav1.7 mutation-related neuropathy, these findings underscore LCM's translational potential as a dual-acting disease-modifying therapy for OA. LCM is a dual-acting Nav1.7 inhibitor that alleviates pain and modifies OA progression. Collagen II-based intra-articular delivery enhances efficacy and supports clinical translation as a noninvasive, non-opioid disease-modifying therapy. © 2026 The Authors.

OBJECTIVE: Osteoarthritis (OA) involves an inflammatory imbalance, yet key mediators and their interplay with potential therapeutics like artemisinin (ART) remain poorly understood. This study aimed to systematically investigate these relationships using Mendelian randomization and to decipher their functional interactions through cellular and molecular experiments, complemented by network pharmacology and molecular docking analyses. METHODS: Using the Mendelian randomization (MR) method, we integrated independent exposure-outcome genome-wide association study data to evaluate the causal association between inflammatory cytokines and OA. Chondrocytes were treated with IL-1β, TGF-β1 (5 μg/mL), and ART (4 μg/mL) for 24 hours. Cell proliferation was assessed using CCK-8 and EdU assays, and gene/protein expression was analyzed via RT-qPCR, Western blotting, and immunofluorescence staining. In parallel, network pharmacology was performed to identify putative ART targets related to OA and to characterize enriched pathways and hub genes through GO/KEGG enrichment and protein-protein interaction (PPI) analyses. Molecular docking was further conducted to evaluate the binding feasibility between ART and the catabolic mediator MMP-13. RESULTS: MR revealed a positive association between TGF-β1 and OA risk (OR = 1.0526, P = 0.0182). Functionally, ART significantly enhanced chondrocyte proliferation, whereas TGF-β1 inhibited it. ART downregulated IL-1β and MMP13 expression, while TGF-β1 upregulated them, indicating opposing effects in OA chondrocytes. Network pharmacology suggested that ART-related OA targets were enriched in inflammation-associated processes and signaling pathways (e.g., MAPK signaling), with PPI analysis highlighting inflammatory signaling hubs (e.g., JAK/STAT-related nodes). Consistently, molecular docking demonstrated favorable binding of ART within the MMP-13 active pocket, supporting the structural feasibility of an ART-MMP-13 interaction. CONCLUSION: This study demonstrates that TGF-β1 plays an important pathogenic role in OA, as supported by MR and in vitro evidence, while ART exhibits anti-inflammatory and anti-catabolic effects by counteracting TGF-

The increasing prevalence and incidence urge efficient treatment of osteoarthritis (OA). In contrast, a single modality is hard to combat OA's complicated pathogenesis and achieve comprehensive chondroprotective function. Through RNA sequencing, we identified bone marrow mesenchymal stromal cell-derived exosomes (BMSC-Exo) and cartilage progenitor cell-derived exosomes (CPC-Exo) have distinct enrichment of miRNA contents, emphasizing macrophage and chondrocyte modulation, respectively. Thus, inspiring us to develop a bi-exosome combination strategy, which combines anti-inflammatory BMSC-Exo and anti-catabolic CPC-Exo, to alleviate osteoarthritis progression via simultaneous regulation of macrophage polarization and chondrocyte phenotype. Once delivered into the rat knee joint cavity by hyaluronic acid methacryloyl microspheres, the bi-exosome combination remarkably postponed OA progression via combating the joint inflammatory and catabolic environment, in which the dominant interventive pathways (i.e., miR-708-5p/NRP-1, miR-431/BRCA-1/PLK-1, and miR-7a-5p/NOTCH-3) were further revealed. This work presents the tailoring of exosome compositions to modulate multitargeting, thereby creating a potential for OA treatment. © 2025 The Authors.

Osteoarthritis (OA) represents a significant challenge in both orthopedic research and clinical practice, necessitating the development of effective therapeutic strategies. Here, we describe an ex vivo model based on osteochondral (OCh) explants housed in a three-dimensional printed device that enables the separation of bone and cartilage compartments. Our model demonstrates effective partitioning, as confirmed by significant differences in measurements of tissue-specific markers. The markers included matrix metalloproteinase (MMP) activity and sulfated glycosaminoglycan (sGAG) release for cartilage and alkaline phosphatase (ALP) activity, tartrate-resistant acid phosphatase (TRAP) activity, and osteocalcin (OC) levels for bone. The cartilage compartment of OCh explants was exposed to inflammatory stimuli, to mimic the OA-related microenvironment, using 10 ng/mL TNFα and 1 ng/mL IL-1β. Cytokine administration was coupled with secretome (or conditioned medium, CM) treatment obtained from 5 × 105 naïve or cytokine-primed adipose-derived mesenchymal cells (CM and pCM). After 3 days, inflammatory cytokines induced a significant upregulation of MMP activity, effectively countered by both CM and pCM, alongside a modest increase in sGAG release. No major changes were detected in the bone counterpart. This study holds dual significance: firstly, the development and preliminary assessment of a human-based ex vivo model in accordance with 3Rs (Replacement, Reduction, Refinement) principles in preclinical research; secondarily, the evidence of an anti-catabolic potential of the adipose-derived mesenchymal cell secretome contributes, within a broader research context, to hypothesizing its potentiality in counteracting OA-associated hallmarks, with possible applications at early onset to mitigate the degenerative processes of this pathology. Trial Registration: ClinicalTrials.gov identifier: NCT04223622.

BACKGROUND: Intervertebral disc (IVD) degeneration is a major contributor to low back pain, yet its initiating factors remain unclear. While the individual effects of pro-inflammatory cytokines and mechanical loading on IVDs have been studied, their combined impact is poorly understood. This study investigated how dynamic compression and torsion interact with interleukin-1 beta (IL-1β) and its inhibitor, interleukin-1 receptor antagonist (IL-1Ra), using bovine IVDs in an ex vivo organ culture system. METHODS: Whole bovine caudal IVDs were cultured for one week in a custom bioreactor applying diurnal dynamic compression (0.1-0.5 MPa) and torsion (±6°) under three media conditions: physiological, catabolic (10 ng/mL IL-1β), and inhibitory (10 ng/mL IL-1Ra). Static compression (0.1 MPa) served as control. 3 T magnetic resonance imaging (MRI) was used pre- and post-culture for imaging and segmentation using 3DSlicer. Subject-personalized finite element (FE) models were generated via morphing algorithms and coupled with a parallel network (PN) model to analyze metabolite transport and its impact on gene expression. Outcomes included disc height, glycosaminoglycan (GAG) content, qPCR, and cell metabolic activity. RESULTS & CONCLUSIONS: Degenerative changes were detected in all treatment groups. Results of decreased disc height, hydration, and ACAN expression, alongside increased MMP-13, indicated that the applied loading was supraphysiological and induced catabolic responses. IL-1Ra, at the given dose, did not counteract degeneration. MRI-based FE modeling effectively captured patterns of tissue consolidation and degeneration, providing valuable insights into IVD responses under combined mechanical and inflammatory stress. This integrative platform highlights the importance of modeling complex IVD environments and may inform the design of improved anti-catabolic therapies. © 2026 The Author(s). JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.

Osteoporosis, characterized by diminished bone density and compromised microstructure, presents a significant healthcare challenge, particularly in the aging population. The primary approach in addressing osteoporosis involves the use of anti-resorptive agents as well as medications that promote bone formation. However, these therapies have limitations, prompting the exploration of novel therapeutic targets. Prolyl Endopeptidase (PREP), an endopeptidase with diverse roles in neuronal peptide metabolism and various physiological processes, has emerged as a potential player in osteoporosis, though its mechanistic involvement remains largely uncharted. This study delves into the role of PREP in osteoporosis, aiming to unravel its underlying mechanisms and therapeutic potential. Utilizing murine models and cellular experiments, we systematically investigate how PREP influences osteoblast differentiation and osteoporosis pathogenesis. Our results suggest activation of the Wnt pathway counteracts the inhibitory effects of PREP deletion on osteoblast differentiation. Additionally, we observe that PREP affects osteoclastogenesis, influencing osteoclast differentiation and bone resorption capacity. Moreover, our investigation extends to age-related osteoporosis, demonstrating PREP's potential therapeutic efficacy beyond estrogen-deficiency-induced osteoporosis. In summary, this study advances our understanding of PREP's multifaceted role in osteoporosis pathogenesis. It underscores PREP as a potential therapeutic target for osteoporosis, offering fresh perspectives on its etiology and treatment. © 2025. The Author(s).

DCSTAMP serves as a critical fusogenic protein orchestrating cell-cell fusion during osteoclastogenesis. The disruption of DCSTAMP functionality preserves preosteoclasts, thereby augmenting bone mass through both anabolic and anti-catabolic mechanisms. Despite its therapeutic potential, specific DCSTAMP inhibitors remain undiscovered. Here we used structure-based virtual screening utilizing AlphaFold predictions to identify a novel small molecule, E8431, which selectively targets the endoplasmic domain of DCSTAMP. In vitro investigations confirm E8431's capacity to impede preosteoclast fusion, concurrently inhibiting bone resorption while stimulating PDGFBB secretion, thus promoting osteogenic and angiogenic processes. We further elucidated a previously uncharacterized DCSTAMP signaling cascade involving DCSTAMP-RAP1B interaction, which activates RAP1-RAC1 signaling-dependent cytoskeletal reorganization. Notably, E8431 demonstrates potent inhibitory effects on this DCSTAMP-RAP1B molecular interface. Moreover, E8431 administration effectively attenuates ovariectomy-induced bone loss in murine models without apparent toxicity, underscoring its potential as a therapeutic agent for osteoporosis. © 2025. The Author(s).

Osteoarthritis (OA) is a chronic degenerative joint disease that lacks effective therapies to halt its progression. While endogenous purinergic signaling-particularly via adenosine-shows promise for reducing inflammation, it is limited by short half-life and off-target effects. To address these limitations, we developed an optimal anti-inflammatory adenosine-guanosine-based oligonucleotide encapsulated in poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NanoOligo) to enhance in vivo stability and investigated its impact on surgically induced OA models and the underlying mechanisms responsible for its anabolic effects. A large oligonucleotide library (482 unique 10- to 20-mer sequences) was screened in RAW264.7 macrophages under LPS-induced inflammation to identify the most potent candidate, which was then encapsulated into PLGA nanoparticles using a microfluidic system. NanoOligo significantly protected against cartilage degeneration and alleviated pain behaviors in the rat ACLT + pMx model following intra-articular administration. In IL-1β-treated chondrocytes, it markedly suppressed inflammatory cytokines (TNFα, IL-6) and catabolic proteases (MMP-3, MMP-13, ADAMTS5). Mechanistically, NanoOligo's anti-catabolic effects were dependent on A1R and A2AR, leading to activation of the PKA-CREB axis and suppression of p38 MAPK signaling, which in turn reduced oxidative stress and cellular senescence via upregulation of the Sirt1-Nrf2-HO-1 antioxidant pathway. Collectively, these findings support joint-localized purinergic modulation as a potential therapeutic target for OA treatment, aligning structural protection with improvements in pain-related behaviors. © 2025. The Author(s).

β-Hydroxy-β-methylbutyrate (HMB), a natural metabolite derived from the essential amino acid leucine, is primarily recognised for its anabolic and anti-catabolic effects on skeletal muscle tissue. Recent studies indicate that HMB may also play a role in influencing the structural organisation of extracellular matrix (ECM) components, particularly collagen, which is crucial for maintaining the mechanical integrity of connective tissues. In this investigation, bovine type I collagen was polymerised in the presence of two concentrations of HMB (0.025 M and 0.25 M) to explore its potential function as a molecular modulator of fibrillogenesis. The morphology of the resulting collagen fibres and their molecular architecture were examined using atomic force microscopy (AFM) and Fourier-transform infrared (FTIR) spectroscopy. The findings demonstrated that lower levels of HMB facilitated the formation of more regular and well-organised fibrillar structures, exhibiting increased D-band periodicity and enhanced stabilisation of the native collagen triple helix, as indicated by Amide I and III band profiles. Conversely, higher concentrations of HMB led to significant disruption of fibril morphology and alterations in secondary structure, suggesting that HMB interferes with the self-assembly of collagen monomers. These structural changes are consistent with a non-covalent influence on interchain interactions and fibril organisation, to which hydrogen bonding and short-range electrostatics may contribute. Collectively, the results highlight the potential of HMB as a small-molecule regulator for soft-tissue matrix engineering, extending its consideration beyond metabolic supplementation towards controllable, materials-oriented modulation of ECM structure.

Sarcopenia, a progressive decline in skeletal muscle mass and function, has emerged as a critical geriatric syndrome affecting 10-40% of older adults, contributing to increased disability and mortality. This comprehensive review evaluates evidence-based strategies for sarcopenia management, from established interventions to emerging personalized approaches. Pathophysiological insights reveal multifactorial mechanisms involving anabolic resistance, chronic inflammation (elevated IL-6, TNF-α), hormonal imbalances (e.g., testosterone/IGF-1 decline), neuromuscular junction dysfunction, mitochondrial impairment, and novel mediators like GDF-15, which drive proteolysis and appetite suppression. Non-pharmacological interventions demonstrate robust efficacy: combined resistance-aerobic exercise regimens (2-3 sessions/week) improve muscle strength by 20-35%, while optimized protein intake (1.0-1.5 g/kg/day) with leucine or vitamin D supplementation enhances muscle synthesis and functional capacity. Pharmacological trials highlight selective androgen receptor modulators (SARMs) and myostatin inhibitors (e.g., bimagrumab) increasing lean mass by 3-5% in phase II studies, with GDF-15-neutralizing antibodies emerging as promising anti-catabolic agents. Advanced therapies, including stem cell transplantation and AAV-mediated gene editing targeting myostatin/IGF-1 pathways, show preclinical regenerative potential. However, clinical translation requires validation through large-scale trials. Personalized strategies integrating biomarkers, comorbidities, and digital monitoring tools optimize intervention efficacy, particularly in complex populations like diabetic or cachectic patients. This synthesis underscores the paradigm shift toward precision medicine but identifies critical knowledge gaps, including long-term safety of biologics and cost-effectiveness of regenerative approaches. Future research should prioritize multimodal therapies, validated biomarkers, and AI-driven algorithms to individualize sarcopenia management in aging populations.

Androgenic-anabolic steroids (AAS) are widely missed worldwide as performance-enhancing agents. The use of AAS started in competitive sports and spread to non-competitive athletes. The World Anti-Doping Agency banned AAS in the 1950s and has continued adding new methods and new variations of AAS. Currently, the Centers for Disease Control and Prevention estimates that the majority of AAS users are adolescent males. The hypothalamus is the integrating center for the reproductive axis (HPG). It receives signals from the amygdala, olfactory, and visual cortex. Gonadotropin-releasing hormone (GnRH) then gets released into a venous portal system that carries it to the adenohypophysis of the pituitary gland. In addition to signals from the central nervous system, humoral factors from the testes also play a role in modulating the release of GnRH. Gonadotropin-releasing hormone release is pulsatile, seasonal, and circadian. Levels of GnRH are highest during spring and in the morning, with peaks occurring every 90 to 120 minutes. Once released, GnRH acts on the pituitary gland and promotes the production and release of luteinizing hormone (LH) and, to a lesser extent, follicle-stimulating hormone (FSH). Luteinizing hormone, in turn, acts on Leydig cells in the testes, which are the site of production of most of the endogenous androgens. Androgen production also occurs in the adrenal cortex, and the conversion of androstenedione peripherally. Testosterone, in turn, inhibits the production of GnRH in the hypothalamus. Testosterone is a 19-carbon steroid and is the most potent endogenous androgen. As such, it is the basis of most AAS. The addition of various functional groups to this basic 19-carbon structure changes the androgenic, anabolic, and toxicity profiles of AAS. Testosterone and other AAS act to increase muscle hypertrophy through modulating androgen receptors and their interaction with co-activators. It also increased muscle hypertrophy through modulation of receptor expression through intercellular metabolism, an anti-catabolic effect, by interfering with glucocorticoid receptor expression and various genomic and non-genomic pathways that act on the central nerv

The purpose of this review is to describe the present evidence for exercise and nutritional interventions as potential contributors in the treatment of sarcopenia and frailty (i.e. muscle mass and physical function decline) and the risk of cardiorenal metabolic comorbidity in people with heart failure (HF). Evidence primarily from cross-sectional studies suggests that the prevalence of sarcopenia in people with HF is 37% for men and 33% for women, which contributes to cardiac cachexia, frailty, lower quality of life, and increased mortality rate. We explored the impact of resistance and aerobic exercise, and nutrition on measures of sarcopenia and frailty, and quality of life following the assessment of 35 systematic reviews and meta-analyses. The majority of clinical trials have focused on resistance, aerobic, and concurrent exercise to counteract the progressive loss of muscle mass and strength in people with HF, while promising effects have also been shown via utilization of vitamin D and iron supplementation by reducing tumour necrosis factor-alpha (TNF-a), c-reactive protein (CRP), and interleukin-6 (IL-6) levels. Experimental studies combining the concomitant effect of exercise and nutrition on measures of sarcopenia and frailty in people with HF are scarce. There is a pressing need for further research and well-designed clinical trials incorporating the anabolic and anti-catabolic effects of concurrent exercise and nutrition strategies in people with HF. © 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

It is well established that creatine supplementation, primarily when combined with resistance training, significantly increases measures of muscle mass and performance (primarily strength). Emerging research also indicates that creatine supplementation may have favorable effects on measures of bone biology. These anabolic adaptations may be related to creatine influencing cellular hydration status, high-energy phosphate metabolism, growth factors, muscle protein kinetics, and the bone remodeling process. Accumulating research also suggests that creatine supplementation has anti-inflammatory and anti-catabolic properties, which may help create a favorable environment for muscle and bone accretion and recovery from exercise. Creatine supplementation has the ability to decrease markers of inflammation and possibly attenuate cancerous tumor growth progression. From a musculoskeletal perspective, there is some evidence to show that creatine supplementation reduces measures of muscle protein catabolism (primarily in males) and bone resorption when combined with resistance training. The purpose of this brief review is to summarize the current body of literature examining the potential anti-inflammatory and anti-catabolic effects of creatine supplementation across various research populations.

92. J Spec Oper Med. 2021 Spring;21(1):78-85. doi: 10.55460/YZI5-1NMV. Applications of Fish Oil Supplementation for Special Operators. Heileson JL, Funderburk LK, Cardaci TD. Fish oil supplementation (FOS) is beneficial for human health and various disease states. FOS has recently received attention related to its anabolic and anti-catabolic effects on skeletal muscle and cognitive performance. Since Special Operations Forces (SOF) personnel endure rigorous combat and training environments that are mentally and physically demanding, FOS may have important applications for the SOF Warfighter. The purpose of this narrative review is to explore the evidence for FOS and its application to multiple physiological and psychological contexts experienced by SOF personnel. For physical performance, FOS may promote lean body mass (LBM) accretion; however, there seems to be minimal impact on strength, power, or endurance. During physiological stress, FOS may preserve strength, power, LBM (during muscle disuse, not weight loss) and enhance recovery. For cognition, FOS likely improves reaction time, mental fatigue, and may reduce the incidence and severity of mild traumatic brain injury; however, FOS has minimal impact on attentional control and mood states. No safety concerns were evident. In conclusion, there are multiple applications of FOS for SOF personnel. Due to the minimal safety concerns and potential anabolic, anti-catabolic and cognitive benefits, FOS is a viable method to promote and sustain SOF Warfighter physical and cognitive performance. Although promising, the FOS trials to date have not been conducted in the context of the multi-stressor environments experienced by SOF personnel, thus, future studies should be conducted in a SOF population. 2021.

In osteoarthritis (OA), inhibition of excessively expressed pro-inflammatory cytokines in the OA joint and increasing the anabolism for cartilage regeneration are necessary. In this ex-vivo study, we used an inflammatory model of human OA chondrocytes microtissues, consisting of treatment with cytokines (interleukin 1β (IL-1β)/tumor necrosis factor α (TNF-α)) with or without supplementation of six herbal compounds with previously identified chondroprotective effect. The compounds were assessed for their capacity to modulate the key catabolic and anabolic factors using several molecular analyses. We selectively investigated the mechanism of action of the two most potent compounds Vanillic acid (VA) and Epimedin C (Epi C). After identification of the anti-inflammatory and anabolic properties of VA and Epi C, the Ingenuity Pathway Analysis showed that in both treatment groups, osteoarthritic signaling pathways were inhibited. In the treatment group with VA, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling was inhibited by attenuation of the nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα) phosphorylation. Epi C showed a significant anabolic effect by increasing the expression of collagenous and non-collagenous matrix proteins. In conclusion, VA, through inhibition of phosphorylation in NF-κB signaling pathway and Epi C, by increasing the expression of extracellular matrix components, showed significant anti-inflammatory and anabolic properties and might be potentially used in combination to treat or prevent joint OA.

BACKGROUND: Cancer Anorexia Cachexia Syndrome (CACS) is a distinct atrophy disease negatively influencing multiple aspects of clinical care and patient quality of life. Although it directly causes 20% of all cancer-related deaths, there are currently no model systems that encompass the entire multifaceted syndrome, nor are there any effective therapeutic treatments. METHODS: A novel model of systemic metastasis was evaluated for the comprehensive CACS (metastasis, skeletal muscle and adipose tissue wasting, inflammation, anorexia, anemia, elevated protein breakdown, hypoalbuminemia, and metabolic derangement) in both males and females. Ex vivo skeletal muscle analysis was utilized to determine ubiquitin proteasome degradation pathway activation. A novel ketone diester (R/S 1,3-Butanediol Acetoacetate Diester) was assessed in multifaceted catabolic environments to determine anti-atrophy efficacy. RESULTS: Here, we show that the VM-M3 mouse model of systemic metastasis demonstrates a novel, immunocompetent, logistically feasible, repeatable phenotype with progressive tumor growth, spontaneous metastatic spread, and the full multifaceted CACS with sex dimorphisms across tissue wasting. We also demonstrate that the ubiquitin proteasome degradation pathway was significantly upregulated in association with reduced insulin-like growth factor-1/insulin and increased FOXO3a activation, but not tumor necrosis factor-α-induced nuclear factor-kappa B activation, driving skeletal muscle atrophy. Additionally, we show that R/S 1,3-Butanediol Acetoacetate Diester administration shifted systemic metabolism, attenuated tumor burden indices, reduced atrophy/catabolism and mitigated comorbid symptoms in both CACS and cancer-independent atrophy environments. CONCLUSIONS: Our findings suggest the ketone diester attenuates multifactorial CACS skeletal muscle atrophy and inflammation-induced catabolism, demonstrating anti-catabolic effects of ketone bodies in multifactorial atrophy. © 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.

In this study, 34 Traditional Chinese Medicine (TCM) compounds were screened for potential anabolic and anti-inflammatory properties on human osteoarthritic (OA) chondrocytes. The anabolic effects were assessed by measuring the glycosaminoglycan (GAG) relative to the DNA content using a 3D pellet culture model. The most chondrogenic compounds were tested in an inflammatory model consisting of 3 days of treatment with cytokines (IL-1β/TNF-α) with or without supplementation of TCM compounds. The anti-inflammatory effects were assessed transcriptionally, biochemically and histologically. From the 34 compounds, Vanilic acid (VA), Epimedin A (Epi A) and C (Epi C), 2''-O-rhamnosylicariside II (2-O-rhs II), Icariin, Psoralidin (PS), Protocatechuicaldehyde (PCA), 4-Hydroxybenzoic acid (4-HBA) and 5-Hydroxymethylfurfural (5-HMF) showed the most profound anabolic effects. After induction of inflammation, pro-inflammatory and catabolic genes were upregulated, and GAG/DNA was decreased. VA, Epi C, PS, PCA, 4-HBA and 5-HMF exhibited anti-catabolic and anti-inflammatory effects and prevented the up-regulation of pro-inflammatory markers including metalloproteinases and cyclooxygenase 2. After two weeks of treatment with TCM compounds, the GAG/DNA ratio was restored compared with the negative control group. Immunohistochemistry and Safranin-O staining confirmed superior amounts of cartilaginous matrix in treated pellets. In conclusion, VA, Epi C, PS, PCA, 4-HBA and 5-HMF showed promising anabolic and anti-inflammatory effects.