Degenerative Osteoarthritis Research Articles

MiR203a-3p as a potential biomarker for synovial pathology associated with osteoarthritis: a pilot study.

Osteoarthritis (OA) is a degenerative musculoskeletal disease that significantly impacts the quality of life. Currently, no validated biomarkers for early detection of OA are defined. The possibility of discovering OA biomarkers is the focus of this study. Human primary OA synovial cells (SVs), isolated from discarded joint tissue of patients with Kellgren & Lawrence score (KL) < 3, (mild/moderate) and KL ≥ 3 (severe), were characterized by FACS analysis. Through qRT-PCR and ELISA assays the inflammation, fibrosis status and the different miRNAs expression has been investigated. The role of miR-203a-3p and its precursors were evaluated through gain and loss of function study, IL-1β synoviocytes treatments and methylation analysis of miR203a promoter. The qRT-PCR analysis of miR203a-3p and pre-miR203a on plasma (isolated 24h before surgery, 3days and 1month after surgery) and synovial fluid (recovered during the surgery) were done to support our in vitro data. MiR203a-3p expression is inversely correlated with the aggressiveness of OA, modulating the expression of epithelial to mesenchymal transition (EMT) and pro-inflammatory factors, as well as regulating the expression of secreted protein acidic and rich in cysteine (SPARC) mRNA. Methylation analysis of the miR203a promoter and SVs IL-1β treatment's highlighted the impact of inflammation on miR203a-3p and pre-miR203a expression; as confirmed by both miRNAs detection in biological fluids derived from patients with severe OA. Our preliminary results suggest that miR-203a-3p might be a potential candidate for staging OA progression and a new protective/predictive biomarker for synovial OA degeneration. Further studies are needed to validate its potential impact on OA.

Pattern of Musculoskeletal Manifestation in Patient with Diabetes Mellitus

Background: Diabetic mellitus (DM) both type 1 and type 2 increasing dramatically throughout worldwide. DM involved all the vital organs including musculoskeletal system. Objective: The purpose of study was to find out patterns of musculoskeletal manifestation (MSM) in diabetic patients &amp; to find out a strategy to improve the outcome of the MS complications in patients with Diabetes Mellitus. Material and Methods: This was hospital based observational study conducted on 143 diabetics patients with musculoskeletal manifestations, both men and women (aged e”15- 70 years) visited in outpatient department and hospital admitted patient in a tertiary care of teaching hospital. Patterns were defined by a meticulous history, relevant general and systemic examination &amp; with the aid of musculoskeletal (MS) Function Assessment semi structured Questionnaire. Results: MSM are common among patients with type 2 diabetes Out of 143 patients in our study 103(72.03%) were Male and 40(27.97%) were female, and male –female ratio 2.57:1. The age distribution of study patients was 15 to 70 years. Overall, 72.03.% of patients were among the 40-59 years old and about 20.28% were 60 years and mean age of the patients was 55±5. Above which is statistically significant (P= 0.048). The shoulder involvement as adhesive capsulitis (frozen shoulder) was found among 69(48.25%) on the diabetic cohort and statistically significant (P= &lt;.05) and mostly among the housewife (27.99%) and manual worker like cultivator (13.99%). Degenerative osteoarthritis was commonly associated with MSM with DM than inflammatory arthritis. Conclusion: In our study shows degenerative, non-inflammatory MSM are common among the diabetic patients that leads to significant pain and disability that directly related with poor glycemic control and co-morbidities like stroke and obesity. Early recognition of these complications, and multidisciplinary management between diabetes and rheumatology specialists is necessary to reduce morbidity. EWMCJ Vol. 12, No. 1&amp;2, January-July 2024: 66-69

Key roles of the superficial zone in articular cartilage physiology, pathology, and regeneration.

The superficial zone (SFZ) of articular cartilage is an important interface that isolates deeper zones from the microenvironment of the articular cavity and is directly exposed to various biological and mechanical stimuli. The SFZ is not only a crucial structure for maintaining the normal physiological function of articular cartilage but also the earliest site of osteoarthritis (OA) cartilage degeneration and a major site of cartilage progenitor cells, suggesting that the SFZ might represent a key target for the early diagnosis and treatment of OA. However, to date, SFZ research has not received sufficient attention, accounting for only about 0.58% of cartilage tissue research. The structure, biological composition, function, and related mechanisms of the SFZ in the physiological and pathological processes of articular cartilage remain unclear. This article reviews the key role of the SFZ in articular cartilage physiology and pathology and focuses on the characteristics of SFZ in articular cartilage degeneration and regeneration in OA, aiming to provide researchers with a systematic understanding of the current research status of the SFZ of articular cartilage, hoping that scholars will give more attention to the SFZ of articular cartilage in the future.

An Exploration of Locomotor Syndrome among Geriatric Population – A Narrative Review

A locomotor disability in the geriatric population is a physical condition that impairs mobility and movement in older persons. It is frequently caused by age-related causes such as degenerative diseases, osteoarthritis, or neurological abnormalities. This impairment can have a substantial influence on older people's quality of life by limiting their ability to conduct daily activities independently, such as walking, standing, or climbing stairs. Addressing locomotor impairments in older persons is critical for preserving their mobility, independence, and overall well-being, ultimately improving their quality of life as they age.A comprehensive literature search was conducted, which were sourced from PubMed, google scholar, Japanese government websites, springer link, semantic scholar generated significant studies using the keywords like locomotor disability, older population, mobility, quality of life, aging. We included articles which were published from 2005–2024.Locomotive Syndrome (LS) affects a significant portion of the elderly population, with prevalence ranging from 8.4% to 50.3%, increasing with age and higher in women. It shows the correlations with osteoporosis and sarcopenia, suggesting potential shared risk factors or pathways. By this the older people tend to have lower quality of life, particularly concerning spinal alignment and trunk deformity. Exercise interventions, including locomotive training, aerobic exercise, and muscle training, are suggested for LS prevention. Vitamin D supplementation may benefit bone health and fall prevention in older individuals.Locomotor syndrome is a substantial concern, especially in ageing populations, with considerable implications for quality of life. Its prevalence, which is frequently associated with osteoporosis and sarcopenia, highlights the necessity of preventive measures including exercise and vitamin D supplementation. Recognising the impact of LS on mobility and well-being is critical for establishing focused interventions to prevent and manage its progression, thereby improving the overall health and independence of geriatric population.

Psychosocial impact of scars following total hip arthroplasty: a comparative study of traumatic vs. non-traumatic etiologies.

This study aims to assess the psychosocial impact of the scars resulting from total hip arthroplasties (THA) in terms of internalization and adaptation related to the etiology of the joint damage (traumatic versus non-traumatic) and the specific surgical procedure, by using a modern approach. A prospective study was carried out between October 2020 and September 2022, at the Orthopedics department, Bihor Emergency County Clinical Hospital in Oradea, located in North-west of Romania. Depending on diagnosis, the participants were divided into two relatively homogeneous groups: non-traumatic group with 113 subjects (55.66%) diagnosed with degenerative hip osteoarthritis and traumatic group with 90 (44.33%) patients who underwent total hip arthroplasty (THA) following a trauma. The highest internalization score was noted in uncemented THA cases performed as a consequence of traumatic coxarthrosis. The ANOVA coefficients of intergroup comparisons for the participants with traumatic coxarthrosis indicate that surgical procedures have a significant influence on scar internalization [F (2, 90) = 10.046; p<0.001; η2=0.188]. Scheffe's post hoc test indicated that patients with non-traumatic coxarthrosis who underwent uncemented THA procedures presented a higher level of psychosocial internalization compared to those who underwent cemented (Mdf = 3.87; p<0.02) and revision THA (Mdf = 4.60; p<0.004), but without surprising differences compared to revision of the soft tissue (Mdf = 3.31; p<0.08). The relevance of the coxarthrosis etiology for subsequent surgical interventions was emphasized in this study. Coxarthrosis has a strong impact on the psychosocial internalization of postoperative scars, which indicates a change in the perception of social support as well as the perception of the quality of life.

A Sustained-Release Butyrate Tablet Suppresses Ex Vivo T Helper Cell Activation of Osteoarthritis Patients in a Double-Blind Placebo-Controlled Randomized Trial

Degenerative joint disease osteoarthritis (OA) is characterized by the degeneration of cartilage, synovial inflammation and low-grade systemic inflammation in association with microbial dysbiosis and intestinal barrier defects. Butyrate is known for its anti-inflammatory and barrier protective effects and might benefit OA patients. In a double-blind placebo-controlled randomized trial, the effects of four to five weeks of oral treatment with sustained-release (SR) butyrate tablets (600 mg/day) on systemic inflammation and immune function were studied in hand OA patients. Serum markers for systemic inflammation and lipopolysaccharide (LPS) leakage were measured and ex vivo stimulation of whole blood or peripheral blood mononuclear cells (PBMCs) was performed at baseline and after treatment. Butyrate treatment did not affect the serum markers nor the cytokine release of ex vivo LPS-stimulated whole blood or PBMCs nor the phenotype of restimulated monocytes. By contrast, butyrate treatment reduced the percentage of activated T helper (Th) cells and the Th17/Treg ratio in αCD3/CD28-activated PBMCs, though cytokine release upon stimulation remained unaffected. Nevertheless, the percentage of CD4+IL9+ cells was reduced by butyrate as compared to the placebo. In both groups, the frequency of Th1, Treg, Th17, activated Th17, CD4+IFNγ+ and CD4+TNFα+ cells was reduced. This study shows a proof of principle of some immunomodulatory effects using a SR butyrate treatment in hand OA patients. The inflammatory phenotype of Th cells was reduced, as indicated by a reduced percentage of Th9 cells, activated Th cells and improved Th17/Treg balance in ex vivo αCD3/CD28-activated PBMCs. Future studies are warranted to further optimize the butyrate dose regime to ameliorate inflammation in OA patients.

Native intra-articular knee microbiome is a matter of facts: a systematic review of clinical evidence.

Growing interest surrounds the role of human gut microbiome in the development of degenerative pathologies such as osteoarthritis (OA), but microbes have recently been detected also in other sites previously considered to be sterile. Evidence emerged suggesting that even native and osteoarthritic knee joints may host several microbial species possibly involved in the osteoarthritic degeneration. This is the first systematic review critically collecting all the available evidence on the existence and composition of knee intra-articular microbiome. A systematic research on the PubMed, Cochrane and Google Scholar databases was performed. Human clinical studies investigating the presence of intra-articular microbiome in native osteoarthritic knee joints with next-generation sequencing techniques were collected. A total of eight studies were included reporting data on 255 knees. All the included studies reported evidence supporting the existence of an intra-articular microbiome in native knee joints, with detection rates varying from 5.8% to 100%. Bacteria from the Proteobacteria phylum were found to be among the most identified followed by the Actinobacteria, Firmicutes, Fusobacteria, and Bacteroideta phyla. Proteobacteria phylum were also found to be more common in osteoarthritic knees when compared to healthy joints. Furthermore, several pathways correlating those microbes to knee OA progression have been suggested and summarized in this review. Evidence collected in this systematic review suggests that the native knee joint, previously presumed to be a sterile environment, hosts a peculiar intra-articular microbiome with a unique composition. Furthermore, its alteration may have a link with the progression of knee osteoarthritis.

The relationship between sarcopenic obesity and degenerative osteoarthritis in older adults

The relationship between sarcopenic obesity and degenerative osteoarthritis in older adults

Yiqi Yangxue formula inhibits cartilage degeneration in knee osteoarthritis by regulating LncRNA-UFC1/miR-34a/MMP-13 axis

Ethnopharmacological relevanceKnee osteoarthritis (KOA) is a prevalent and disabling clinical condition affecting joint structures worldwide. The Yiqi Yangxue formula (YQYXF) is frequently prescribed in clinical settings for the treatment of KOA. Existing research has primarily focused on alterations in drug metabolism, with limited investigation into the epigenetic effects of YQYXF, particularly in relation to non-coding RNA. Aim of the studyExploring the effects of YQYXF on critical factors of long chain non-coding RNA UFC1/miR-34a/matrix metalloproteinase-13 (MMP-13) axis and their interrelationships. MethodsUHPLC-QE-MS technology was used to identify the YQYXF ingredients in rat serum. KEGG and GO analysis were performed on the targets of blood components acting on KOA using a database. Simultaneously, a protein interaction network was constructed using target proteins and metabolites to identify the core components and key pathways of YQYXF. The KOA rat model was established using an improved Hulth method. SPF SD rats were randomly divided into normal group, sham surgery group, model group, celecoxib capsules group (18 mg/kg), YQYXF low, medium and high dose groups (4.6g/kg, 9.2g/kg, 18.4g/kg). Observe the synovial and cartilage tissues of rats using pathological methods. RT-PCR was used to detect the levels of UFC1, miR-34a, and MMP-13 in cartilage. Immunohistochemistry was used to detect the levels of MMP-13 and ADAMTS-5 in cartilage. ELISA method was used to detect the levels of MMP-13 and ADAMTS-5 in serum. In addition, we further validated the regulation of crucial factor expression levels of UFC1/miR-34a/MMP-13 axis in rat chondrocytes and degenerative chondrocytes of KOA patients by YQYXF, providing a basis for its treatment of KOA. ResultsThe compounds that YQYXF enters the bloodstream mainly contain flavonoids and phenylpropanoid compounds. The core components that act on OA include quercetin, fisetin, and demethylweldelolactone. The main target pathways are the IL-17 signaling pathway, lipid and atherosclerosis, cellular sensitivity, inflammatory mediator regulation of TRP channels, TNF signaling pathway, relaxin signaling pathway and C-type lectin receptor signaling pathway. YQYXF inhibited the expression of miR-34a and MMP-13 mRNA, and reduced the protein levels of MMP-13 and ADAMTS-5. In vitro studies have confirmed that 20% YQYXF serum promoted UFC1 and reduce miR-34a levels. In addition, miR-34a in sh-UFC1+10% YQYXF serum and sh-UFC1+20% YQYXF serum groups significantly decreased compared to the sh-UFC1 group. ConclusionThe anti-KOA cartilage degeneration effect of YQYXF might be related to inhibiting cell apoptosis and promoting cell proliferation, which regulated the lncRNA-UFC1/miR-34a/MMP-13 axis.

Efficacy, Safety, and Economic Feasibility of Dokhwalgisaeng-Tang for Degenerative Knee Osteoarthritis: Protocol for a Multicenter, Randomized, Assessor Blinded, Controlled Trial.

Knee osteoarthritis (KOA) is one of the most prevalent degenerative joint diseases worldwide. The herbal decoction, Dokhwalgisaeng-tang (DHGST), has been commonly used in East Asia to treat osteoarthritis. However, there is insufficient evidence to draw clear conclusions concerning its effectiveness and safety for patients with KOA. We aim to determine the efficacy, safety, and economic feasibility of DHGST compared with Celecoxib, an oral COX-2 inhibitor, for patients with degenerative KOA. This multicenter, randomized, noninferiority trial, involving 160 participants who will be randomized using block randomization with 1:1 allocation, will compare DHGST and Celecoxib. The total trial period is 24weeks after random allocation, comprising 12weeks of treatment and 12weeks of follow-up. Participants with KOA will be administered 200 mg of DHGST (treatment group) or Celecoxib capsules (control group) for 12weeks. Efficacy and safety evaluations will be conducted at weeks 0, 4, 8, and 12, and 24. The primary outcome measurement is the Korean Western Ontario McMaster score at week 12. Changes in pain intensity using a 100 mm visual analog scale, changes in quality of life using a EuroQol 5-dimension 5-level self-report survey, and patient satisfaction will also be measured to evaluate effectiveness between the two groups. A trial-based economic feasibility evaluation will be conducted to analyze treatment cost-effectiveness from societal and healthcare system perspectives. Drug safety will be assessed through adverse reactions and laboratory test findings. This trial protocol has the following limitations. Applying a double-dummy design is not possible, as the tablet and granule forms can easily be distinguished visually, and achieving participant blinding is challenging. The trial findings are intended to inform participants, physicians, and other stakeholders in determining whether DHGST could be used as an alternative therapeutic option for KOA. KCT0008424 (Clinical Research Information Service of the Republic of Korea), registered on 12 May 2023.

Matrix Viscoelasticity Tunes the Mechanobiological Behavior of Chondrocytes.

In articular cartilage, the pericellular matrix acting as a specialized mechanical microenvironment modulates environmental signals to chondrocytes through mechanotransduction. Matrix viscoelastic alterations during cartilage development and osteoarthritis (OA) degeneration play an important role in regulating chondrocyte fate and cartilage matrix homeostasis. In recent years, scientists are gradually realizing the importance of matrix viscoelasticity in regulating chondrocyte function and phenotype. Notably, this is an emerging field, and this review summarizes the existing literatures to the best of our knowledge. This review provides an overview of the viscoelastic properties of hydrogels and the role of matrix viscoelasticity in directing chondrocyte behavior. In this review, we elaborated the mechanotransuction mechanisms by which cells sense and respond to the viscoelastic environment and also discussed the underlying signaling pathways. Moreover, emerging insights into the role of matrix viscoelasticity in regulating chondrocyte function and cartilage formation shed light into designing cell-instructive biomaterial. We also describe the potential use of viscoelastic biomaterials in cartilage tissue engineering and regenerative medicine. Future perspectives on mechanobiological comprehension of the viscoelastic behaviors involved in tissue homeostasis, cellular responses, and biomaterial design are highlighted. Finally, this review also highlights recent strategies utilizing viscoelastic hydrogels for designing cartilage-on-a-chip.

9. Chronic knee pain.

Chronic knee pain is defined as pain that persists or recurs over 3 months. The most common is degenerative osteoarthritis (OA). This review represents a comprehensive description of the pathology, diagnosis, and treatment of OA of the knee. The literature on the diagnosis and treatment of chronic knee pain was retrieved and summarized. A modified Delphi approach was used to formulate recommendations on interventional treatments. Patients with knee OA commonly present with insidious, chronic knee pain that gradually worsens. Pain caused by knee OA is predominantly nociceptive pain, with occasional nociplastic and infrequent neuropathic characteristics occurring in a diseased knee. A standard musculoskeletal and neurological examination is required for the diagnosis of knee OA. Although typical clinical OA findings are sufficient for diagnosis, medical imaging may be performed to improve specificity. The differential diagnosis should exclude other causes of knee pain including bone and joint disorders such as rheumatoid arthritis, spondylo- and other arthropathies, and infections. When conservative treatment fails, intra-articular injections of corticosteroids and radiofrequency (conventional and cooled) of the genicular nerves have been shown to be effective. Hyaluronic acid infiltrations are conditionally recommended. Platelet-rich plasma infiltrations, chemical ablation of genicular nerves, and neurostimulation have, at the moment, not enough evidence and can be considered in a study setting. The decision to perform joint-preserving and joint-replacement options should be made multidisciplinary. When conservative measures fail to provide satisfactory pain relief, a multidisciplinary approach is recommended including psychological therapy, integrative treatments, and procedural options such as intra-articular injections, radiofrequency ablation, and surgery.

Effect of Danhong Injection on Articular Cartilage Degeneration in Rabbits with Knee Osteoarthritis

The aim of this research was to investigate the effect of Danhong injection nanoparticle (DIN) plus warm acupuncture (WA) on articular cartilage degeneration in knee osteoarthritis (KOA) rabbits. First, the KOA model and DIN were made. After success, the rabbits were randomly grouped: according to the treatment methods: controls, DIN, WA, and DIN+WA groups, with 10 rabbits in each group. The controls did not receive any treatment, and the other groups received corresponding treatment intervention, respectively. Through treatment, articular cartilage samples were collected. The bone morphology, LequesneMG score, Mankin score were analyzed. The safranin-fast green, toluidine blue, Terminal Deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling (TUNEL), and immunohistochemical staining were observed. The levels of apoptosis-related factors were determined. The results showed that the KOA rabbit model and DIN were successfully constructed. Compared with other groups, the LequesneMG and Mankin scores of DIN+WA group decreased markedly (P &lt; 0.05). Safranin-fast green and toluidine blue staining showed that the number of chondrocytes in DIN+WA group was markedly increased, which was more as against other groups. TUNEL staining revealed that the number of apoptotic chondrocytes was markedly reduced, and the apoptotic index was markedly lower in DIN+WA group as against other three groups (P &lt; 0.05). Compared with other groups, Bax and Caspase-3 were markedly decreased, and Bcl-2 was markedly raised in DIN+WA group (P &lt; 0.05). According to the review, the combined application of DIN and WA can promote the growth of chondrocytes, inhibit the apoptosis of chondrocytes, and effectively improve the degeneration of knee articular cartilage, which has application value.

TRNA-derived fragment 3031B regulates human anterior cruciate ligament cell proliferation and survival by targeting RELA

tRNA-derived fragments (tRFs) are novel short noncoding RNAs that play pivotal roles in cell proliferation and survival. However, knowledge of the biological roles of tRFs in anterior cruciate ligament (ACL) cells is limited. Here, we intended to investigate the function of tRF-3031B in ACL cell. We used the tRF and tiRNA array to analyze tRF and tiRNA expression profiles in osteoarthritis (OA) ACL cells and normal ACL cells, and qRT-PCR and fluorescence in situ hybridization (FISH) were used to determine tRF-3031B expression. The results showed that tRF-3031B was expressed at low levels in OA ACL and Interleukin-1β (IL-1β) treated ACL cells. We found that RELA was the target of tRF-3031B. When ACL cells were transfected with tRF-3031B mimics, RELA expression was suppressed, whereas transfection with tRF-3031B inhibitors had the opposite effect. The rescue and dual-luciferase reporter assays showed that tRF-3031B silenced the RELA expression by binding to its untranslated region (3′-UTR). Hence, this study showed the novel function of tRF-3031B in regulating ACL cell proliferation and survival by targeting RELA, and these findings may offer a new direction for the study of ACL degeneration and pathophysiological of OA.

Two Members of Vitamin-K-Dependent Proteins, Gla-Rich Protein (GRP) and Matrix Gla Protein (MGP), as Possible New Players in the Molecular Mechanism of Osteoarthritis.

Objectives: The pathophysiology of osteoarthritis is mainly unknown. Matrix Gla protein (MGP) and Gla-rich protein (GRP) are both vitamin-K-dependent mineralization inhibitors. In this study, we aimed to compare the levels of MGP and GRP in the synovial fluid of osteoarthritic (OA) and non-osteoarthritic (non-OA) knee joints. Materials and Methods: Two groups were formed, with one consisting of patients with OA and the other non-OA, serving as a control group. The non-OA group included individuals who had arthroscopic surgery for non-cartilage-related issues. In the OA group, all participants had undergone total knee arthroplasty because of grade 4 primary degenerative osteoarthritis. During the operation, at least 1 mL of knee synovial fluid was collected. The GRP and MGP levels in the synovial fluid were measured using an ELISA kit. Results: The mean age in the OA group (62.03 ± 11.53 years) was significantly higher than that in the non-OA group (47.70 ± 14.49 years; p = 0.0001). GRP levels were significantly higher in the OA group (419.61 ± 70.14 ng/mL) compared to the non-OA group (382.18 ± 62.34 ng/mL; p = 0.037). MGP levels were significantly higher in the OA group (67.76 ± 11.36 ng/mL) compared to the non-OA group (53.49 ± 18.28 ng/mL; p = 0.001). Calcium levels (Ca++) were also significantly higher in the OA group (12.89 ± 3.43 mg/dL) compared to the non-OA group (9.51 ± 2.15 mg/dL; p = 0.0001). There was a significantly positive correlation between MGP levels and age (p = 0.011, R = +0.335). Linear regression analysis was performed to determine the effect of age on MGP levels (p = 0.011, R-Square = 0.112). The dependent variable in this analysis was MGP (ng/mL), and age was the predictor. Conclusions: In conclusion, both GRP and MGP are potentially usable biomarkers in osteoarthritis. However, GRP seems to be more valuable because it is not associated with age. In the future, both proteins could provide important contributions to the diagnosis and treatment of osteoarthritis.

TRPA1 aggravates osteoclastogenesis and osteoporosis through activating endoplasmic reticulum stress mediated by SRXN1

Osteoporosis (OP) is a disorder of bone remodeling caused by an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Therefore, inhibiting excessive osteoclast activity is one of the promising strategies for treating OP. A major transient receptor potential cation channel, known as transient receptor potential ankyrin 1 (TRPA1), was found to alleviate joint pain and cartilage degeneration in osteoarthritis. However, little research has focused on TRPA1 function in OP. As a result, this study aimed to explore the TRPA1 characteristics and its potential therapeutic function during osteoclastogenesis. The TRPA1 expression gradually increased in the osteoclast differentiation process; however, its suppression with small interfering RNA and an inhibitor (HC030031) significantly controlled the osteoclast count and the expression of osteoclast characteristic genes. Its suppression also inhibited endoplasmic reticulum (ER) stress-related pancreatic ER kinase (PERK) pathways. An ER stress inhibitor (thapsigargin) reversed the down-regulated levels of ER stress and osteoclast differentiation by suppressing TRPA1. Transcriptome sequencing results demonstrated that TRPA1 negatively regulated reactive oxygen species (ROS) and significantly increased the expression of an antioxidant gene, SRXN1. The osteoclast differentiation and the levels of ER stress were enhanced with SRXN1 inhibition. Finally, TRPA1 knockdown targeting macrophages by adeno-associated virus-9 could relieve osteoclast differentiation and osteopenia in ovariectomized mice. In summary, silencing TRPA1 restrained osteoclast differentiation through ROS-mediated down-regulation of ER stress via inhibiting PERK pathways. The study also indicated that TRPA1 might become a prospective treatment target for OP.

The Hounsfield Unit Values of Talar Subchondral Bone Predict Articular Cartilage Degeneration in Patients With Ankle Osteoarthritis.

Therapeutic strategies for ankle osteoarthritis (OA) are determined based on OA staging, alignment, and articular cartilage conditions. However, it is difficult to evaluate the degeneration of the remaining cartilage using imaging modalities. Subchondral bone plays a crucial role in maintaining cartilage homeostasis. Measurement of local Hounsfield unit (HU) values allows for the quantitative assessment of small changes in the subchondral bone. This study aimed to evaluate a relationship between the HU values of the subchondral bone and the histologic findings of articular cartilage in ankle OA. The talar articular surface was harvested from 14 ankles during arthroplasty. The talus was divided into anterior, middle, and posterior parts, and histologic specimens were prepared. Safranin O staining was performed and histologic findings were evaluated using the modified Mankin score. The regions of interest (ROIs) were set in the medial, central, and lateral regions of the specimens and computed tomography (CT) images, and the relationship between the HU values and histologic findings was analyzed. As OA progressed, cartilage defects increased. In conjunction with cartilage degeneration, the subchondral bone plate thickened, and the HU values increased. The HU value significantly and positively correlated with the modified Mankin score (r = 0.756), subchondral bone thickness (r = 0.674, P < .01), and trabecular bone area (r = 0.637). The cutoff HU values were 594 (sensitivity, 0.813; specificity, 0.944) for 3 points and 727 (sensitivity, 0.929; specificity, 0.782) for 11 points on the modified Mankin score. Significant correlations between HU values and cartilage degeneration in ankle OA were noted. Measuring HU values on CT images can be useful for evaluating the joint surface condition, including histologic findings of the remaining cartilage.

Phillyrin: A potential therapeutic agent for osteoarthritis via modulation of NF-κB and Nrf2 signaling pathways

Osteoarthritis (OA) is the predominant cause of disability among elderly people worldwide and is characterized by cartilage degeneration and excessive bone formation. Phillyrin, derived from forsythia, is a key extract renowned for its pronounced antibacterial and anti-inflammatory effects. Forsythia, deeply integrated into traditional Oriental medicine, has historically been utilized for its various pharmacological effects, including antibacterial, anti-inflammatory, and hepato-protective properties. Nevertheless, the anti-inflammatory impact of phillyrin on the progression of osteoarthritis remains enigmatic. The objective of this research was to assess the anti-inflammatory and anti-aging properties of phillyrin in mouse chondrocytes induced by IL-1β, as well as to elucidate the fundamental mechanisms underlying the phenomenon at play. Additionally, the investigation extends to observing the impact of phillyrin by establishing a murine osteoarthritic model. The ultimate goal was to identify phillyrin as a potential antiosteoarthritic agent. This investigation employs a multifaceted approach. Initially, key action targets of phillyrin, along with its probable action pathways, were identified by molecular docking and network pharmacological techniques. These findings were subsequently confirmed through both in vivo and in vitro studies. Network pharmacological analysis revealed NFE2L2 (NRF2), NFKB1, TLR4, and SERPING1 as pivotal candidate targets for the treatment of osteoarthritis with phillyrin. Molecular docking revealed hydrogen bond interactions between phillyrin and Arg415, Arg483, Ser508, and Asn387 on the Nrf2 receptor, while electrostatic interactions occurred with residues Arg415 and Arg380. Experiments conducted in vitro indicated that phillyrin preconditioning hindered the IL-1β-induced expression of proinflammatory factors which included TNF-α, COX-2, IL-6, and iNOS. Furthermore, phillyrin counteracts the IL-1β-induced degradation of aggrecan and collagen II within the extracellular matrix (ECM). This protective action is caused by the inhibition of the NF-κB pathway by phillyrin. Additionally, the mitigation of chondrocyte aging by phillyrin was observed. Our investigation revealed that phillyrin mitigates inflammation and counteracts cartilage degeneration in osteoarthritis (OA) patients by suppressing inflammation in chondrocytes and impeding aging through suppression of the NF-κB pathway.

Human adipose and synovial-derived MSCs synergistically attenuate osteoarthritis by promoting chondrocyte autophagy through FoxO1 signaling

BackgroundHuman adipose-derived stem cells (ADSCs) exert a strong anti-inflammatory effect, and synovium-derived stem cells (SDSCs) have high chondrogenic potential. Thus, this study aims to investigate whether a combination of human ADSCs and SDSCs will have a synergistic effect that will increase the chondrogenic potential of osteoarthritis (OA) chondrocytes in vitro and attenuate the cartilage degeneration of early and advanced OA in vitro.MethodsADSCs, SDSCs, and chondrocytes were isolated from OA patients who underwent total knee arthroplasty. The ADSCs–SDSCs mixed cell ratios were 1:0 (ADSCs only), 8:2, 5:5 (5A5S), 2:8, and 0:1 (SDSCs only). The chondrogenic potential of the OA chondrocytes was evaluated in vitro with a transwell assay or pellet culture with various mixed cell groups. The mixed cell group with the highest chondrogenic potential was then selected and injected into the knee joints of nude rats of early and advanced OA stages in vivo. The animals were then evaluated 12 and 20 weeks after surgery through gait analysis, von frey test, microcomputed tomography, MRI, and immunohistochemical and histological analyses. Finally, the mechanisms underlying these findings were investigated through the RNA sequencing of tissue samples in vivo and Western blot of the OA chondrocyte autophagy pathway.ResultsAmong the MSCs treatment groups, 5A5S had the greatest synergistic effect that increased the chondrogenic potential of OA chondrocytes in vitro and inhibited early and advanced OA in vivo. The 5A5S group significantly reduced cartilage degeneration, synovial inflammation, pain sensation, and nerve invasion in subchondral nude rat OA, outperforming both single-cell treatments. The underlying mechanism was the activation of chondrocyte autophagy via the FoxO1 signaling pathway.ConclusionA combination of human ADSCs and SDSCs demonstrated higher potential than a single type of stem cell, demonstrating potential as a novel treatment for OA.

Mass Spectrometry Imaging of the Subchondral Bone in Osteoarthritis Reveals Tissue Remodeling of Extracellular Matrix Proteins that Precede Cartilage Loss.

Osteoarthritis (OA) of the knee is a degenerative condition of the skeletal extracellular matrix (ECM) marked by the loss of articular cartilage and subchondral bone homeostasis. Treatments for OA in the knee beyond full joint replacement are lacking primarily due to gaps in molecular knowledge of the biological drivers of disease. Here, Mass Spectrometry Imaging (MSI) enabled molecular spatial mapping of the proteomic landscape of human knee tissues. Histologic sections of human tibial plateaus from OA patients and cadaveric controls were treated with collagenase III to target ECM proteins prior to imaging using a timsTOF fleX mass spectrometer (Bruker) for matrix-assisted laser desorption ionization (MALDI)-MSI of bone and cartilage proteins in human knees. Spatial MSI data of the knee, using sections of the tibial plateau from non-arthritic, cadaveric donors or from knee replacement patients with medial OA were processed and automatically segmented identifying distinct areas of joint damage. ECM peptide markers compared either OA to cadaveric tissues or OA medial to OA lateral. Not only did candidate peptides distinguish OA relative to intact cartilage, but also emphasized a significant spatial difference between OA and intact subchondral bone (AUROC >0.85). Overall, 31 peptide candidates from ECM proteins, including COL1A1, COL3A1, and unanticipated detection of collagens COL6A1 and COL6A3 in adult bone, exhibited significantly elevated abundance in diseased tissue. Highly specific hydroxyproline-containing collagens dominated OA subchondral bone directly under regions of lost cartilage revealing dramatic tissue remodeling providing molecular details on the progression of joint degeneration in OA. The identification of specific spatial markers for the progression of subchondral bone degeneration in OA advances our molecular understanding of coupled deterioration of joint tissues.