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Osteoarthritis: From Pathogenesis to Treatment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (29 February 2024) | Viewed by 16205

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Dr. Francesca Oliviero

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Rheumatology Unit, Department of Medicine DIMED, University of Padova, 35128 Padova, Italy
Interests: pathogenetic mechanisms in crystal-induced inflammation; the role of calcium crystals in osteoarthritis; biomarkers in psoriatic arthritis; synovial fluid analysis; the influence of bioactive compounds in inflammation and crystal-induced arthritis; diet in rheumatic diseases
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Roberta Ramonda

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Rheumatology Unit, Department of Medicine - DIMED, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy
Interests: spondyloarthritis; osteoarthritis; crystal-induced arthritis; biomarkers in synovial fluid; biologics; ultrasonography

Special Issue Information

Dear Colleagues,

Osteoarthritis is the most common arthropathy among adults worldwide. Causing pain and disabilities, it constitutes an important social and economic burden to healthcare systems. No effective pharmacological treatments are currently available to cure osteoarthritis, so prevention remains the most important strategy to mitigate the disease development and progression. During the last few years, advances in translational research have allowed the definition of new molecular mechanisms responsible for dysregulated pathways in osteoarthritis, and thanks to high-throughput technologies, new potential therapeutic targets have been identified. Further research should be promoted in this field in order to make osteoarthrits a curable disease.

This Special Issue aims to collect contributions on new physiopathological mechanisms, target molecules, or biomarkers in osteoarthritis.

Dr. Francesca Oliviero
Prof. Dr. Roberta Ramonda
Guest Editors

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Keywords

osteoarthritis
inflammation
pain
calcium crystals
synovial fluid
animal models of osteoarthritis
omics technologies

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Published Papers (9 papers)

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Research

32 pages, 15556 KiB

Open AccessArticle

Network Pharmacology and Experimental Verifications to Discover Scutellaria baicalensis Georgi’s Effects on Joint Inflammation, Destruction, and Pain in Osteoarthritis

by Hee-Geun Jo, Chae-Yun Baek, Ho Sueb Song and Donghun Lee

Int. J. Mol. Sci. 2024, 25(4), 2127; https://doi.org/10.3390/ijms25042127 - 9 Feb 2024

Cited by 6 | Viewed by 1945

Abstract

Osteoarthritis is the most common type of arthritis, characterized by joint pain and a decline in physiological function. Scutellaria baicalensis Georgi (SB) is potentially effective against osteoarthritis because of its wide range of anti-inflammatory pharmacological activities. This study aimed to identify the mode of action of SB against osteoarthritis using network pharmacology prediction and experimental verification. Networks were constructed to key compounds, hub targets, and pathways essential for SB’s effectiveness against osteoarthritis. Additionally, in vivo and in vitro tests were performed, including investigations on weight bearing in hind limbs, the acetic acid-induced writhing response, lipopolysaccharide-stimulated RAW264.7 cells, and serum cytokine responses. We identified 15 active compounds and 14 hub targets, supporting the anti-osteoarthritis effects of SB. The Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that fluid shear stress, atherosclerosis, phosphatidylinositol 3-kinase-Akt signaling, and cellular senescence pathways were important. SB showed substantial anti-inflammatory, analgesic, and joint tissue-protective effects against osteoarthritis. Our study shows that SB has the potential value to be further investigated as a candidate material for the treatment of osteoarthritis in the future. Full article

(This article belongs to the Special Issue Osteoarthritis: From Pathogenesis to Treatment)

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11 pages, 3990 KiB

Open AccessArticle

Synovial Fluid from Patients with Osteoarthritis Shows Different Inflammatory Features Depending on the Presence of Calcium Pyrophosphate Crystals

by Francesca Oliviero, Chiara Baggio, Marta Favero, Amelia Carmela Damasco, Carlotta Boscaro, Davide Tietto, Mattia Albiero, Andrea Doria and Roberta Ramonda

Int. J. Mol. Sci. 2024, 25(1), 393; https://doi.org/10.3390/ijms25010393 - 27 Dec 2023

Cited by 1 | Viewed by 1492

Abstract

The role of calcium pyrophosphate (CPP) crystals in osteoarthritis (OA) is still a matter of debate. With this study we aimed to investigate the inflammatory features of synovial fluid (SF) collected from patients with OA with CPP crystals compared with those without crystals. We also explored the effect of OA SF on monocytes response. SFs were collected from adult patients with OA and subdivided according to the presence of crystals. Local cellular and humoral inflammatory mediators were analysed in the SF samples. The expression levels of IL-1β, IL-18, CASP-1, NLRP3, and GAPDH were measured by RT-PCR in the cells obtained by pelleting the SF samples. For the in vitro study, a monocytic cell line was treated with selected SF samples. SF with CPP crystals showed a significant increase in inflammatory cellular indices and higher levels of IL-1β, IL-8, and caspase-1 transcript with respect to SF without crystals. Higher concentrations of VEGF were also observed in the early stages of the whole OA patients. THP-1 cells stimulated with OA SF released a significant amount of IL-1 β in culture supernatants. This study demonstrated that SF collected from patients with OA shows different inflammatory features depending on the presence of CPP crystals. Full article

(This article belongs to the Special Issue Osteoarthritis: From Pathogenesis to Treatment)

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18 pages, 1445 KiB

Open AccessArticle

Face and Predictive Validity of MI-RAT (Montreal Induction of Rat Arthritis Testing), a Surgical Model of Osteoarthritis Pain in Rodents Combined with Calibrated Exercise

by Colombe Otis, Emilie Bouet, Sokhna Keita-Alassane, Marilyn Frezier, Aliénor Delsart, Martin Guillot, Agathe Bédard, Jean-Pierre Pelletier, Johanne Martel-Pelletier, Bertrand Lussier, Francis Beaudry and Eric Troncy

Int. J. Mol. Sci. 2023, 24(22), 16341; https://doi.org/10.3390/ijms242216341 - 15 Nov 2023

Cited by 1 | Viewed by 1656

Abstract

Validating animal pain models is crucial to enhancing translational research and response to pharmacological treatment. This study investigated the effects of a calibrated slight exercise protocol alone or combined with multimodal analgesia on sensory sensitivity, neuroproteomics, and joint structural components in the MI-RAT model. Joint instability was induced surgically on day (D) 0 in female rats (N = 48) distributed into sedentary–placebo, exercise–placebo, sedentary–positive analgesic (PA), and exercise–PA groups. Daily analgesic treatment (D3–D56) included pregabalin and carprofen. Quantitative sensory testing was achieved temporally (D–1, D7, D21, D56), while cartilage alteration (modified Mankin’s score (mMs)) and targeted spinal pain neuropeptide were quantified upon sacrifice. Compared with the sedentary–placebo (presenting allodynia from D7), the exercise–placebo group showed an increase in sensitivity threshold (p < 0.04 on D7, D21, and D56). PA treatment was efficient on D56 (p = 0.001) and presented a synergic anti-allodynic effect with exercise from D21 to D56 (p < 0.0001). Histological assessment demonstrated a detrimental influence of exercise (mMs = 33.3%) compared with sedentary counterparts (mMs = 12.0%; p < 0.001), with more mature transformations. Spinal neuropeptide concentration was correlated with sensory sensitization and modulation sites (inflammation and endogenous inhibitory control) of the forced mobility effect. The surgical MI-RAT OA model coupled with calibrated slight exercise demonstrated face and predictive validity, an assurance of higher clinical translatability. Full article

(This article belongs to the Special Issue Osteoarthritis: From Pathogenesis to Treatment)

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14 pages, 2754 KiB

Open AccessArticle

Comparison of Four Treatment Protocols with Intra-Articular Medium Molecular Weight Hyaluronic Acid in Induced Temporomandibular Osteoarthritis: An Experimental Study

by Schilin Wen, Veronica Iturriaga, Bélgica Vásquez and Mariano del Sol

Int. J. Mol. Sci. 2023, 24(18), 14130; https://doi.org/10.3390/ijms241814130 - 15 Sep 2023

Cited by 3 | Viewed by 1363

Abstract

The aim was to compare the effect between a single intra-articular infiltration (1i) and two infiltrations (2i) of medium molecular weight hyaluronic acid (MMW-HA) of high viscosity (HV) and low viscosity (LV) on the histopathological characteristics of temporomandibular joint (TMJ) osteoarthritis (OA) induced in rabbits. An experimental study was conducted on Oryctolagus cuniculus rabbits, including 42 TMJs, distributed between (1) TMJ-C, control group; (2) TMJ-OA, group with OA; (3) TMJ-OA-wt, group with untreated OA; (4) group treated with HA-HV-1i; (5) group treated with HA-HV-2i; (6) group treated with HA-LV-1i; and (7) group treated with HA-LV-2i. The results were evaluated using the Osteoarthritis Research Society International (OARSI) scale and descriptive histology considering the mandibular condyle (MC), the articular disc (AD), and the mandibular fossa (MF). The Kruskal–Wallis test was used for the statistical analysis, considering p < 0.05 significant. All treated groups significantly decreased the severity of OA compared to the TMJ-OA-wt group. The HA-HV-2i group showed significant differences in the degree of OA from the TMJ-OA group. The degree of OA in the HA-HV-2i group was significantly lower than in the HA-LV-1i, HA-LV-2i, and HA-HV-1i groups. The protocol that showed better results in repairing the joint was HA-HV-2i. There are histological differences depending on the protocol of the preparation used: two infiltrations seem to be better than one, and when applying two doses, high viscosity shows better results. Full article

(This article belongs to the Special Issue Osteoarthritis: From Pathogenesis to Treatment)

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19 pages, 3750 KiB

Open AccessArticle

Effect of Targeted Cytokine Inhibition on Progression of Post-Traumatic Osteoarthritis Following Intra-Articular Fracture

by Michael S. Valerio, Jorge B. Edwards, Connor P. Dolan, Jessica M. Motherwell, Benjamin K. Potter, Christopher L. Dearth and Stephen M. Goldman

Int. J. Mol. Sci. 2023, 24(17), 13606; https://doi.org/10.3390/ijms241713606 - 2 Sep 2023

Cited by 3 | Viewed by 1970

Abstract

Intra-articular fractures (IAF) result in significant and prolonged inflammation, increasing the chances of developing post-traumatic osteoarthritis (PTOA). Interleukin-one beta (IL-1β) and Tumor Necrosis Factor-alpha (TNF-α) are key inflammatory factors shown to be involved in osteochondral degradation following IAF. As such, use of targeted biologics such as Infliximab (INX), a TNF-α inhibitor, and Anakinra (ANR), an interleukin-one (IL-1) receptor antagonist (IL1RA), may protect against PTOA by damping the inflammatory response to IAF and reducing osteochondral degradation. To test this hypothesis, IAFs were induced in the hindlimb knee joints of rats treated with INX at 10 mg/kg/day, ANR at 100 g/kg/day, or saline (vehicle control) by subcutaneous infusion for a period of two weeks and healing was evaluated at 8-weeks post injury. Serum and synovial fluid (SF) were analyzed for soluble factors. In-vivo microcomputed tomography (µCT) scans assessed bone mineral density and bone morphometry measurements. Cationic CA4⁺ agent assessed articular cartilage composition via ex vivo µCT. Scoring according to the Osteoarthritis Research Society International (OARSI) guidelines was performed on stained histologic tibia sections at the 56-day endpoint on a 0–6 scale. Systemically, ANR reduced many pro-inflammatory cytokines and reduced osteochondral degradation markers Cross Linked C-Telopeptide Of Type II (CTXII, p < 0.05) and tartrate-resistant acid phosphatase (TRAP, p < 0.05). ANR treatment resulted in increased chemokines; macrophage-chemotractant protein-1 (MCP-1), MPC-3, macrophage inhibitory protein 2 (MIP2) with a concomitant decrease in proinflammatory interleukin-17A (IL17A) at 14 days post-injury within the SF. Microcomputed tomography (µCT) at 56 days post-injury revealed ANR Treatment decreased epiphyseal degree of anisotropy (DA) (p < 0.05) relative to saline. No differences were found with OARSI scoring but contrast-enhanced µCT revealed a reduction in glycosaminoglycan content with ANR treatment. These findings suggest targeted cytokine inhibition, specifically IL-1 signaling, as a monotherapy has minimal utility for improving IAF healing outcomes but may have utility for promoting a more permissive inflammatory environment that would allow more potent disease modifying osteoarthritis drugs to mitigate the progression of PTOA after IAF. Full article

(This article belongs to the Special Issue Osteoarthritis: From Pathogenesis to Treatment)

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17 pages, 2509 KiB

Open AccessArticle

Relations between Structure/Composition and Mechanics in Osteoarthritic Regenerated Articular Tissue: A Machine Learning Approach

by Matteo Berni, Francesca Veronesi, Milena Fini, Gianluca Giavaresi and Gregorio Marchiori

Int. J. Mol. Sci. 2023, 24(17), 13374; https://doi.org/10.3390/ijms241713374 - 29 Aug 2023

Cited by 3 | Viewed by 1317

Abstract

In the context of a large animal model of early osteoarthritis (OA) treated by orthobiologics, the purpose of this study was to reveal relations between articular tissues structure/composition and cartilage viscoelasticity. Twenty-four sheep, with induced knee OA, were treated by mesenchymal stem cells in various preparations—adipose-derived mesenchymal stem cells (ADSCs), stromal vascular fraction (SVF), and amniotic endothelial cells (AECs)—and euthanized at 3 or 6 months to evaluate the (i) biochemistry of synovial fluid; (ii) histology, immunohistochemistry, and histomorphometry of articular cartilage; and (iii) viscoelasticity of articular cartilage. After performing an initial analysis to evaluate the correlation and multicollinearity between the investigated variables, this study used machine learning (ML) models—Variable Selection Using Random Forests (VSURF) and Extreme Gradient Boosting (XGB)—to classify variables according to their importance and employ them for interpretation and prediction. The experimental setup revealed a potential relation between cartilage elastic modulus and cartilage thickness (CT), synovial fluid interleukin 6 (IL6), and prostaglandin E2 (PGE2), and between cartilage relaxation time and CT and PGE2. SVF treatment was the only limit on the deleterious OA effect on cartilage viscoelastic properties. This work provides indications to future studies aiming to highlight these and other relationships and focusing on advanced regeneration targets. Full article

(This article belongs to the Special Issue Osteoarthritis: From Pathogenesis to Treatment)

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13 pages, 1769 KiB

Open AccessArticle

Changes in the Subchondral Bone, Visfatin, and Cartilage Biomarkers after Pharmacological Treatment of Experimental Osteoarthritis with Metformin and Alendronate

by Sevdalina Nikolova Lambova, Nina Ivanovska, Stela Stoyanova, Lyudmila Belenska-Todorova, Elenka Georgieva, Tsvetelina Batsalova, Dzhemal Moten, Desislava Apostolova and Balik Dzhambazov

Int. J. Mol. Sci. 2023, 24(12), 10103; https://doi.org/10.3390/ijms241210103 - 14 Jun 2023

Cited by 3 | Viewed by 1773

Abstract

Subchondral bone that has intense communication with the articular cartilage might be a potential target for pharmacological treatment in the early stages of osteoarthritis (OA). Considering the emerging data about the role of adipokines in the pathogenesis of OA, the administration of drugs that influence their level is also intriguing. Metformin and alendronate were administered in mice with collagenase-induced OA (CIOA) as a monotherapy and in combination. Safranin O staining was used for the assessment of changes in subchondral bone and articular cartilage. Before and after treatment, serum levels of visfatin and biomarkers of cartilage turnover (CTX-II, MMP-13, and COMP) were assessed. In the current study, the combined administration of alendronate and metformin in mice with CIOA led to the protection against cartilage and subchondral bone damage. In mice with CIOA, metformin led to a decrease in visfatin level. In addition, treatment with metformin, alendronate, or their combination lowered the level of cartilage biomarkers (CTX-II and COMP), while the level of MMP-13 was not influenced. In conclusion, personalized combination treatment in OA according to clinical phenotype, especially in the early stages of the disease, might lead to the identification of a successful disease-modifying therapeutic protocol in OA. Full article

(This article belongs to the Special Issue Osteoarthritis: From Pathogenesis to Treatment)

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15 pages, 4850 KiB

Open AccessArticle

CD11b Deficiency Favors Cartilage Calcification via Increased Matrix Vesicles, Apoptosis, and Lysyl Oxidase Activity

by Ilaria Bernabei, Uwe Hansen, Driss Ehirchiou, Jürgen Brinckmann, Veronique Chobaz, Nathalie Busso and Sonia Nasi

Int. J. Mol. Sci. 2023, 24(11), 9776; https://doi.org/10.3390/ijms24119776 - 5 Jun 2023

Cited by 1 | Viewed by 1930

Abstract

Pathological cartilage calcification is a hallmark feature of osteoarthritis, a common degenerative joint disease, characterized by cartilage damage, progressively causing pain and loss of movement. The integrin subunit CD11b was shown to play a protective role against cartilage calcification in a mouse model of surgery-induced OA. Here, we investigated the possible mechanism by which CD11b deficiency could favor cartilage calcification by using naïve mice. First, we found by transmission electron microscopy (TEM) that CD11b KO cartilage from young mice presented early calcification spots compared with WT. CD11b KO cartilage from old mice showed progression of calcification areas. Mechanistically, we found more calcification-competent matrix vesicles and more apoptosis in both cartilage and chondrocytes isolated from CD11b-deficient mice. Additionally, the extracellular matrix from cartilage lacking the integrin was dysregulated with increased collagen fibrils with smaller diameters. Moreover, we revealed by TEM that CD11b KO cartilage had increased expression of lysyl oxidase (LOX), the enzyme that catalyzes matrix crosslinks. We confirmed this in murine primary CD11b KO chondrocytes, where Lox gene expression and crosslinking activity were increased. Overall, our results suggest that CD11b integrin regulates cartilage calcification through reduced MV release, apoptosis, LOX activity, and matrix crosslinking. As such, CD11b activation might be a key pathway for maintaining cartilage integrity. Full article

(This article belongs to the Special Issue Osteoarthritis: From Pathogenesis to Treatment)

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10 pages, 416 KiB

Open AccessArticle

The Association between Oxytocin and Lower Limb Osteoarthritis: A Prospective Cohort Study

by Christian Hubert Roux, Anne-Sophie Rousseau, Antonio Iannelli, Nadine Gautier, Stéphanie Ferrero, Charlotte Hinault, Giulia Chinetti, Willy Ngueyon-Sime, Francis Guillemin and Ez Zoubir Amri

Int. J. Mol. Sci. 2023, 24(11), 9750; https://doi.org/10.3390/ijms24119750 - 5 Jun 2023

Viewed by 1805

Abstract

Oxytocin (OT), a neuropeptide best known for its role in emotional and social behaviors, has been linked to osteoarthritis (OA). This study aimed to investigate the serum OT level in hip and/or knee OA patients and to study its association with disease progression. Patients from the KHOALA cohort with symptomatic hip and/or knee OA (Kellgren and Lawrence (KL) scores of 2 and 3) and follow-up at 5 years were included in this analysis. The primary endpoint was structural radiological progression, which was defined as an increase of at least one KL point at 5 years. Logistic regression models were used to estimate the associations between OT levels and KL progression while controlling for gender, age, BMI, diabetes and leptin levels. Data from 174 hip OA patients and 332 knee OA patients were analyzed independently. No differences in OT levels were found between the ‘progressors’ and ‘non-progressors’ groups among the hip OA patients and knee OA patients, respectively. No statistically significant associations were found between the OT levels at baseline and KL progression at 5 years, the KL score at baseline or the clinical outcomes. Higher structural damage at baseline and severe structural progression of hip and knee osteoarthritis did not appear to be associated with a low serum OT level at baseline. Full article

(This article belongs to the Special Issue Osteoarthritis: From Pathogenesis to Treatment)

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