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Cellular & Molecular Biology Letters Sep 2023During aging and after traumatic injuries, cartilage and bone cells are exposed to various pathophysiologic mediators, including reactive oxygen species (ROS),... (Review)
Review
During aging and after traumatic injuries, cartilage and bone cells are exposed to various pathophysiologic mediators, including reactive oxygen species (ROS), damage-associated molecular patterns, and proinflammatory cytokines. This detrimental environment triggers cellular stress and subsequent dysfunction, which not only contributes to the development of associated diseases, that is, osteoporosis and osteoarthritis, but also impairs regenerative processes. To counter ROS-mediated stress and reduce the overall tissue damage, cells possess diverse defense mechanisms. However, cellular antioxidative capacities are limited and thus ROS accumulation can lead to aberrant cell fate decisions, which have adverse effects on cartilage and bone homeostasis. In this narrative review, we address oxidative stress as a major driver of pathophysiologic processes in cartilage and bone, including senescence, misdirected differentiation, cell death, mitochondrial dysfunction, and impaired mitophagy by illustrating the consequences on tissue homeostasis and regeneration. Moreover, we elaborate cellular defense mechanisms, with a particular focus on oxidative stress response and mitophagy, and briefly discuss respective therapeutic strategies to improve cell and tissue protection.
Topics: Humans; Reactive Oxygen Species; Oxidative Stress; Osteoarthritis; Cell Differentiation; Osteoporosis; Cellular Senescence
PubMed: 37777764
DOI: 10.1186/s11658-023-00489-y -
Annals of the Rheumatic Diseases May 2024Hip and knee osteoarthritis (OA) are increasingly common with a significant impact on individuals and society. Non-pharmacological treatments are considered essential to...
INTRODUCTION
Hip and knee osteoarthritis (OA) are increasingly common with a significant impact on individuals and society. Non-pharmacological treatments are considered essential to reduce pain and improve function and quality of life. EULAR recommendations for the non-pharmacological core management of hip and knee OA were published in 2013. Given the large number of subsequent studies, an update is needed.
METHODS
The Standardised Operating Procedures for EULAR recommendations were followed. A multidisciplinary Task Force with 25 members representing 14 European countries was established. The Task Force agreed on an updated search strategy of 11 research questions. The systematic literature review encompassed dates from 1 January 2012 to 27 May 2022. Retrieved evidence was discussed, updated recommendations were formulated, and research and educational agendas were developed.
RESULTS
The revised recommendations include two overarching principles and eight evidence-based recommendations including (1) an individualised, multicomponent management plan; (2) information, education and self-management; (3) exercise with adequate tailoring of dosage and progression; (4) mode of exercise delivery; (5) maintenance of healthy weight and weight loss; (6) footwear, walking aids and assistive devices; (7) work-related advice and (8) behaviour change techniques to improve lifestyle. The mean level of agreement on the recommendations ranged between 9.2 and 9.8 (0-10 scale, 10=total agreement). The research agenda highlighted areas related to these interventions including adherence, uptake and impact on work.
CONCLUSIONS
The 2023 updated recommendations were formulated based on research evidence and expert opinion to guide the optimal management of hip and knee OA.
Topics: Humans; Osteoarthritis, Knee; Osteoarthritis, Hip; Exercise Therapy; Patient Education as Topic; Europe; Self-Management; Self-Help Devices; Evidence-Based Medicine; Weight Loss
PubMed: 38212040
DOI: 10.1136/ard-2023-225041 -
Nature Communications Oct 2023Osteoarthritis (OA) is characterised by an irreversible degeneration of articular cartilage. Here we show that the BMP-antagonist Gremlin 1 (Grem1) marks a bipotent...
Osteoarthritis (OA) is characterised by an irreversible degeneration of articular cartilage. Here we show that the BMP-antagonist Gremlin 1 (Grem1) marks a bipotent chondrogenic and osteogenic progenitor cell population within the articular surface. Notably, these progenitors are depleted by injury-induced OA and increasing age. OA is also caused by ablation of Grem1 cells in mice. Transcriptomic and functional analysis in mice found that articular surface Grem1-lineage cells are dependent on Foxo1 and ablation of Foxo1 in Grem1-lineage cells caused OA. FGFR3 signalling was confirmed as a promising therapeutic pathway by administration of pathway activator, FGF18, resulting in Grem1-lineage chondrocyte progenitor cell proliferation, increased cartilage thickness and reduced OA. These findings suggest that OA, in part, is caused by mechanical, developmental or age-related attrition of Grem1 expressing articular cartilage progenitor cells. These cells, and the FGFR3 signalling pathway that sustains them, may be effective future targets for biological management of OA.
Topics: Mice; Animals; Osteoarthritis; Stem Cells; Cells, Cultured; Gene Expression Profiling; Osteogenesis; Cartilage, Articular; Chondrocytes; Intercellular Signaling Peptides and Proteins
PubMed: 37907525
DOI: 10.1038/s41467-023-42199-1 -
Advanced Science (Weinheim,... Jul 2023Degenerative musculoskeletal diseases (DMDs), including osteoporosis, osteoarthritis, degenerative disc disease, and sarcopenia, present major challenges in the aging... (Review)
Review
Degenerative musculoskeletal diseases (DMDs), including osteoporosis, osteoarthritis, degenerative disc disease, and sarcopenia, present major challenges in the aging population. Patients with DMDs present with pain, functional decline, and reduced exercise tolerance, which result in long-term or permanent deficits in their ability to perform daily activities. Current strategies for dealing with this cluster of diseases focus on relieving pain, but they have a limited capacity to repair function or regenerate tissue. Cell-based therapies have attracted considerable attention in recent years owing to their unique mechanisms of action and remarkable effects on regeneration. In this review, current experimental attempts to use cell-based therapies for DMDs are highlighted, and the modes of action of different cell types and their derivatives, such as exosomes, are generalized. In addition, the latest findings from state-of-the-art clinical trials are reviewed, approaches to improve the efficiency of cell-based therapies are summarized, and unresolved questions and potential future research directions for the translation of cell-based therapies are identified.
Topics: Humans; Aged; Cell- and Tissue-Based Therapy; Osteoarthritis; Osteoporosis; Regeneration; Pain
PubMed: 37199688
DOI: 10.1002/advs.202207050 -
Journal of Orthopaedics and... Sep 2023Knee osteoarthritis (OA) is a chronic disease associated with a severe impact on quality of life. However, unfortunately, there are no evidence-based guidelines for the... (Review)
Review
BACKGROUND
Knee osteoarthritis (OA) is a chronic disease associated with a severe impact on quality of life. However, unfortunately, there are no evidence-based guidelines for the non-surgical management of this disease. While recognising the gap between scientific evidence and clinical practice, this position statement aims to present recommendations for the non-surgical management of knee OA, considering the available evidence and the clinical knowledge of experienced surgeons. The overall goal is to offer an evidenced-based expert opinion, aiding clinicians in the management of knee OA while considering the condition, values, needs and preferences of individual patients.
METHODS
The study design for this position statement involved a preliminary search of PubMed, Google Scholar, Medline and Cochrane databases for literature spanning the period between January 2021 and April 2023, followed by screening of relevant articles (systematic reviews and meta-analyses). A Società Italiana Ortopedia e Traumatologia (SIOT) multidisciplinary task force (composed of four orthopaedic surgeons and a rheumatologist) subsequently formulated the recommendations.
RESULTS
Evidence-based recommendations for the non-surgical management of knee OA were developed, covering assessment, general approach, patient information and education, lifestyle changes and physical therapy, walking aids, balneotherapy, transcutaneous electrical nerve stimulation, pulsed electromagnetic field therapy, pharmacological interventions and injections.
CONCLUSIONS
For non-surgical management of knee OA, the recommended first step is to bring about lifestyle changes, particularly management of body weight combined with physical exercise and/or hydrotherapy. For acute symptoms, non-steroidal anti-inflammatory drugs (NSAIDs), topic or oral, can be used. Opioids can only be used as third-line pharmacological treatment. Glucosamine and chondroitin are also suggested as chronic pharmacological treatment. Regarding intra-articular infiltrative therapy, the use of hyaluronic acid is recommended in cases of chronic knee OA [platelet-rich plasma (PRP) as second line), in the absence of active acute disease, while the use of intra-articular injections of cortisone is effective and preferred for severe acute symptoms.
Topics: Humans; Osteoarthritis, Knee; Orthopedics; Quality of Life; Traumatology; Knee Joint
PubMed: 37679552
DOI: 10.1186/s10195-023-00729-z -
Osteoporosis International : a Journal... Sep 2023Trabecular bone score (TBS) is a grey-level textural measurement acquired from dual-energy X-ray absorptiometry lumbar spine images and is a validated index of bone...
Update on the clinical use of trabecular bone score (TBS) in the management of osteoporosis: results of an expert group meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), and the International...
PURPOSE
Trabecular bone score (TBS) is a grey-level textural measurement acquired from dual-energy X-ray absorptiometry lumbar spine images and is a validated index of bone microarchitecture. In 2015, a Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) published a review of the TBS literature, concluding that TBS predicts hip and major osteoporotic fracture, at least partly independent of bone mineral density (BMD) and clinical risk factors. It was also concluded that TBS is potentially amenable to change as a result of pharmacological therapy. Further evidence on the utility of TBS has since accumulated in both primary and secondary osteoporosis, and the introduction of FRAX and BMD T-score adjustment for TBS has accelerated adoption. This position paper therefore presents a review of the updated scientific literature and provides expert consensus statements and corresponding operational guidelines for the use of TBS.
METHODS
An Expert Working Group was convened by the ESCEO and a systematic review of the evidence undertaken, with defined search strategies for four key topics with respect to the potential use of TBS: (1) fracture prediction in men and women; (2) initiating and monitoring treatment in postmenopausal osteoporosis; (3) fracture prediction in secondary osteoporosis; and (4) treatment monitoring in secondary osteoporosis. Statements to guide the clinical use of TBS were derived from the review and graded by consensus using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach.
RESULTS
A total of 96 articles were reviewed and included data on the use of TBS for fracture prediction in men and women, from over 20 countries. The updated evidence shows that TBS enhances fracture risk prediction in both primary and secondary osteoporosis, and can, when taken with BMD and clinical risk factors, inform treatment initiation and the choice of antiosteoporosis treatment. Evidence also indicates that TBS provides useful adjunctive information in monitoring treatment with long-term denosumab and anabolic agents. All expert consensus statements were voted as strongly recommended.
CONCLUSION
The addition of TBS assessment to FRAX and/or BMD enhances fracture risk prediction in primary and secondary osteoporosis, adding useful information for treatment decision-making and monitoring. The expert consensus statements provided in this paper can be used to guide the integration of TBS in clinical practice for the assessment and management of osteoporosis. An example of an operational approach is provided in the appendix. This position paper presents an up-to-date review of the evidence base, synthesised through expert consensus statements, which informs the implementation of Trabecular Bone Score in clinical practice.
Topics: Male; Female; Humans; Cancellous Bone; Osteoporosis; Osteoporotic Fractures; Bone Density; Absorptiometry, Photon; Lumbar Vertebrae; Osteoarthritis; Aging; Consensus; World Health Organization; Risk Assessment
PubMed: 37393412
DOI: 10.1007/s00198-023-06817-4 -
Osteoarthritis and Cartilage Feb 2024Biomechanics plays a significant yet complex role in osteoarthritis (OA) onset and progression. Identifying alterations in biomechanical factors and their complex... (Review)
Review
Biomechanics plays a significant yet complex role in osteoarthritis (OA) onset and progression. Identifying alterations in biomechanical factors and their complex interactions is critical for gaining new insights into OA pathophysiology and identification of clearly defined and modifiable mechanical treatment targets. This review synthesized biomechanics studies from March 2022 to April 2023, from which three themes relating to human gait emerged: (1) new insights into the pathogenesis of OA using computational modeling and machine learning, (2) technology-enhanced biomechanical interventions for OA, and (3) out-of-lab biomechanical assessments of OA. We further highlighted future-focused areas which may continue to advance the field of biomechanics in OA, with a particular emphasis on exploiting technology to understand and treat biomechanical mechanisms of OA outside the laboratory. The breadth of studies included in this review highlights the complex role of biomechanics in OA and showcase numerous innovative and outstanding contributions to the field. Exciting cross-disciplinary efforts integrating computational modeling, mobile sensors, and machine learning methods show great promise for streamlining in vivo multi-scale biomechanics workflows and are expected to underpin future breakthroughs in the understanding and treatment of biomechanics in OA.
Topics: Humans; Biomechanical Phenomena; Osteoarthritis; Gait; Machine Learning; Osteoarthritis, Knee
PubMed: 38043858
DOI: 10.1016/j.joca.2023.11.015 -
Bone Research Sep 2023Abnormal subchondral bone remodeling leading to sclerosis is a main feature of osteoarthritis (OA), and osteomodulin (OMD), a proteoglycan involved in extracellular...
Abnormal subchondral bone remodeling leading to sclerosis is a main feature of osteoarthritis (OA), and osteomodulin (OMD), a proteoglycan involved in extracellular matrix mineralization, is associated with the sclerotic phenotype. However, the functions of OMD remain poorly understood, specifically in vivo. We used Omd knockout and overexpressing male mice and mutant zebrafish to study its roles in bone and cartilage metabolism and in the development of OA. The expression of Omd is deeply correlated with bone and cartilage microarchitectures affecting the bone volume and the onset of subchondral bone sclerosis and spontaneous cartilage lesions. Mechanistically, OMD binds to RANKL and inhibits osteoclastogenesis, thus controlling the balance of bone remodeling. In conclusion, OMD is a key factor in subchondral bone sclerosis associated with OA. It participates in bone and cartilage homeostasis by acting on the regulation of osteoclastogenesis. Targeting OMD may be a promising new and personalized approach for OA.
Topics: Male; Animals; Mice; Down-Regulation; Sclerosis; Zebrafish; Proteoglycans; Osteoarthritis
PubMed: 37730805
DOI: 10.1038/s41413-023-00286-5 -
Nature Medicine Dec 2023Various types of cellular injection have become a popular and costly treatment option for patients with knee osteoarthritis despite a paucity of literature establishing... (Randomized Controlled Trial)
Randomized Controlled Trial
Various types of cellular injection have become a popular and costly treatment option for patients with knee osteoarthritis despite a paucity of literature establishing relative efficacy to each other or corticosteroid injections. Here we aimed to identify the safety and efficacy of cell injections from autologous bone marrow aspirate concentrate, autologous adipose stromal vascular fraction and allogeneic human umbilical cord tissue-derived mesenchymal stromal cells, in comparison to corticosteroid injection (CSI). The study was a phase 2/3, four-arm parallel, multicenter, single-blind, randomized, controlled clinical trial with 480 patients with a diagnosis of knee osteoarthritis (Kellgren-Lawrence II-IV). Participants were randomized to the three different arms with a 3:1 distribution. Arm 1: autologous bone marrow aspirate concentrate (n = 120), CSI (n = 40); arm 2: umbilical cord tissue-derived mesenchymal stromal cells (n = 120), CSI (n = 40); arm 3: stromal vascular fraction (n = 120), CSI (n = 40). The co-primary endpoints were the visual analog scale pain score and Knee injury and Osteoarthritis Outcome Score pain score at 12 months versus baseline. Analyses of our primary endpoints, with 440 patients, revealed that at 1 year post injection, none of the three orthobiologic injections was superior to another, or to the CSI control. In addition, none of the four groups showed a significant change in magnetic resonance imaging osteoarthritis score compared to baseline. No procedure-related serious adverse events were reported during the study period. In summary, this study shows that at 1 year post injection, there was no superior orthobiologic as compared to CSI for knee osteoarthritis. ClinicalTrials.gov Identifier: NCT03818737.
Topics: Humans; Osteoarthritis, Knee; Pain; Single-Blind Method; Treatment Outcome
PubMed: 37919438
DOI: 10.1038/s41591-023-02632-w -
Journal of Nanobiotechnology Nov 2023Osteoarthritis (OA) is an age-related disease characterised by the accumulation of senescent chondrocytes, which drives its pathogenesis and progression. Senescent cells...
BACKGROUND
Osteoarthritis (OA) is an age-related disease characterised by the accumulation of senescent chondrocytes, which drives its pathogenesis and progression. Senescent cells exhibit distinct features, including mitochondrial dysfunction and the excessive accumulation and release of reactive oxygen species (ROS), which are highly correlated and lead to a vicious cycle of increasing senescent cells. Stem cell therapy has proven effective in addressing cellular senescence, however, it still has issues such as immune rejection and ethical concerns. Microvesicles (MVs) constitute the primary mechanism through which stem cell therapy exerts its effects, offering a cell-free approach that circumvents these risks and has excellent anti-ageing potential. Nonetheless, MVs have a short in vivo half-life, and their secretion composition varies considerably under diverse conditions. This study aims to address these issues by constructing a ROS-responsive hydrogel loaded with pre-stimulant MVs. Through responding to ROS levels this hydrogel intelligently releases MVs, and enhancing mitochondrial function in chondrocytes to improving cellular senescence.
RESULT
We employed Interferon-gamma (IFN-γ) as a stem cell-specific stimulus to generate IFN-γ-microvesicles (iMVs) with enhanced anti-ageing effects. Simultaneously, we developed a ROS-responsive carrier utilising 3-aminophenylboronic acid (APBA)-modified silk fibroin (SF) and polyvinyl alcohol (PVA). This carrier served to protect MVs, prolong longevity, and facilitate intelligent release. In vitro experiments demonstrated that the Hydrogel@iMVs effectively mitigated cell senescence, improved mitochondrial function, and enhanced cellular antioxidant capacity. In vivo experiments further substantiated the anti-ageing capabilities of the Hydrogel@iMVs.
CONCLUSION
The effect of MVs can be significantly enhanced by appropriate pre-stimulation and constructing a suitable carrier. Therefore, we have developed a ROS-responsive hydrogel containing IFN-γ pre-stimulated iMVs to target the characteristics of ageing chondrocytes in OA for therapeutic purposes. Overall, this novel approach effectively improving mitochondrial dysfunction by regulating the balance between mitochondrial fission and fusion, and the accumulation of reactive oxygen species was reduced, finally, alleviates cellular senescence, offering a promising therapeutic strategy for OA.
Topics: Humans; Reactive Oxygen Species; Hydrogels; Cellular Senescence; Osteoarthritis; Mitochondria
PubMed: 37968657
DOI: 10.1186/s12951-023-02211-8