OA Progression Research Articles

Erosive hand osteoarthritis phenotype: clinical and proteomic characterization

Purpose: Erosive hand osteoarthritis (EHOA) is often considered a more severe form of hand OA that includes pain and inflammation. However, more data are needed regarding the different hand OA phenotypes, especially erosive and non-erosive, to conclude if they represent two different subsets of hand OA or even different degrees of affectation of the same disease. The purpose of this work is to define a specific clinical pattern of patients with EHOA and identify putative biochemical markers associated with this phenotype. Methods: This cross-sectional study was conducted in the Prospective Cohort of Osteoarthritis A Coruna (PROCOAC). This cohort consists of 1136 subjects, from which 834 were diagnosed of hand OA following ACR criteria. After reviewing the x-rays, the cohort was split into patients with and without erosive hand OA. Then, both clinical and demographic data within each group were subsequently analyzed. A Univariate analysis comparing different variables between both groups, followed by a stepwise regression logistic regression analysis was performed to characterize the clinical pattern of EHOA. The identification of biochemical markers was carried out following a two-step workflow: in a first discovery phase, a proteomic approach based on peptide labelling with Isobaric tags for relative and absolute quantitation (iTRAQ) was employed using two different sets of sera (n=20) from EHOA or non-EHOA patients. In a second validation phase an independent set of 346 individual serum samples from the PROCOAC cohort (EHOA, n=127; non-EHOA, n= 219) was used to quantify serum concentrations of the extracellular matrix protein 1 (ECM1) by ELISA. The Mann-Whitney test was carried out in order to look for significant differences between EHOA and non-EHOA groups. All the statistical analyses were performed using SPSS software v.24. Results: The univariate analysis showed that EHOA patients were younger (p<0.001), smokers (p=0.011), with lower both body mass index (p=0.006) and arterial hypertension (p=0.002); increased frequency of inflammatory symptoms in hands (p<0.001), more presence of nodular hand OA (p=0.001) but lower frequency of other forms of hand OA, specially thumb-base (p=0.005) and metacarpophalangeal (p=0.036). In addition, these patients also showed a lower number of damaged joints (p<0.001), specially the knee (p<0.001). The stepwise logistic regression model (Table 1) confirmed the strong association of age (OR=0.963;95%CI=0.937-0.989;p=0.005), inflammatory symptoms (OR=4.575;95%CI=2.621-7.985;p<0.001), increased prevalence of nodal OA (OR=2.125;95%CI=1.118-4.037;p=0.021) and, in patients over 64 years old, MetS (OR=2.029;95%CI=1.183-3.478;p=0.010) with the erosive phenotype. In addition, erosive patients show a lower prevalence of knee OA (OR=0.416;95%CI=0.252-0.687;p=0.001) and to carry this phenotype at baseline does not confer a significant increased risk for radiographic knee OA progression over time). Regarding the proteomic analysis for the identification of potential biomarkers associated with the EHOA phenotype, a total of 257 different proteins were identified in the serum samples with more than two peptides and a total score ≥2 at 95% confidence. Thirty-six proteins were found quantitatively altered between those patients with or without EHOA. A significant reduction (p=0.029) of ECM1 concentrations was found in the serum from patients with the EHOA phenotype (0.154 ± 0.010 μg/ml vs 0.169 ± 0.007 μg/ml) (Figure 1). Conclusions: A specific clinical pattern of patients with EHOA has been defined. It has been associated with altered levels of 36 proteins in serum. Particularly, decreased amounts of ECM1 have been found in patients with this erosive phenotype.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

GG genotype of SNP RS12107036 in TP63 gene increases the risk of rapidly progressive osteoarthritis of the knee. data from the osteoarthritis initiative

Purpose: There is a need to identify patients that experience the rapid progressive phenotype of Osteoarthritis (RPOA) to include them in clinical trials and to implement prevention strategies. During the last years, nuclear single nucleotide polymorphisms (SNPs) have been associated with both susceptibility and progression of the disease, but not with the rapid progression phenotype. Our aim is to analyze the influence of previously knee OA-associated nuclear SNPs on the risk of RPOA of the knee in patients of the OAI. Methods: We selected Caucasian patients from the OAI that were subsequently assigned into three different groups (252 patients each) based on the following criteria: i) rapid progressors, with baseline KL grade 0, 1 in at least one knee and increase up to KL≥ 3 during 48-month follow-up period; or baseline KL grade 2 in at least one knee and increase up to KL 4 or total knee replacement (TKR) during the follow-up. ii) no-rapid progressors, with baseline KL grade 0, 1 in at least one knee and increase up to KL 2 during 48-month follow-up period; or baseline KL grade 2 in at least one knee and increase up to KL 3 during the follow-up. iii) no-progressors, with KL grade 0, 1 or 2 at baseline in at least one knee and bilaterally stable during 48-month follow-up period. Additionally, these groups were re-categorized into two groups: non-progressors and progressors (pooling no-rapid and rapid progressors). Preliminary chi-square analyses and binary and multinomial logistic regression models adjusted by gender, age, body mass index (BMI), contralateral OA, previous injury in target knee and WOMAC pain, were performed. Nuclear SNPs were previously assigned using mini-sequencing techniques. The analyses were performed using IBM SPSS Statistics v24. Results: In this study we analyzed the effect of 7 SNPs that had been strongly associated with knee OA susceptibility in different GWAS studies: rs11177, rs4730250, rs11842874, rs12107036, rs8044769, rs10948172 and rs143383. Chi-square analyses showed that the frequency distribution of rs12107036 was significantly different between groups (p=0,028), being the GG genotype over-represented in the rapid-progressors group and the AA genotype in the non-progressors group (Figure 1). The binary logistic regression showed that G allele appeared significantly over-represented in the (pooled) progressors group when compared with non-progressors (OR 1,682; 95% CI: 1,148-2,463; p=0,008), regardless of gender (OR 2,049; 95% CI 1,478-2,842; p <0,001), BMI (OR 1,085; 95% CI 1,044-1,127; p<0,001), contralateral knee OA (OR 1,400; 95% CI 1,009-1,942; p=0,044), previous injury (OR 1,723; 95% CI 1,223-2,429; p=0,002) and WOMAC pain (OR 1,102; 95% CI 1,033-1,177; p=0,003) (Table 1). On the other hand the multinomial logistic regression showed that, in addition to age (OR 1,064; 95% CI: 1,041-1,088; p<0,001) and previous injury in target knee (OR 1,523; 95% CI: 1,047-2,216; p=0,028), the GG genotype (OR 1,574; 95% CI: 1,039-2,382; p=0,032) emerged as a potential risk factor for the rapid progression phenotype when compared with non-rapid progressors (Table 2). Conclusions: The G allele of the nuclear SNP rs12107036 increases the risk of knee OA progression. Depending on the number of copies of the risk allele the level of progression increases, being the GG genotype a risk factor for the rapidly progressive phenotype of the knee. The assignment of this nuclear polymorphism could be useful as complementary genetic biomarker for the early identification of this OA phenotype.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Synovial inflammation in anterior cruciate ligament injury knees in mice: surgical vs non-surgical models

Purpose: Anterior-cruciate-ligament (ACL) rupture is one of the most common knee injuries, resulting in pain, disability, and increased risk of developing OA. However, only ∼50% of individuals with ACL rupture develop OA, and the factors underlying this variable risk remain unclear. Changes in joint stability as a result of ACL deficiency drive mechanobiological dysfunction and the development of OA. However, specific factors are known to increase OA risk such as concurrent injury to the meniscus, cartilage, and subchondral bone. Also, the degree of initial joint inflammation and its resolution are implicated in long-term outcomes. Surgical and nonsurgical models of ACL rupture in mice result in similar joint instability but distinct risks or trajectories of OA. We used these two models to investigate if differences in synovial inflammatory response are associated with this risk of OA disease progression Methods: Ten-week-old, male C57BL/6 mice were randomly assigned to ACL transection (ACLT), ACL rupture (ACLR), sham-surgery or uninjured groups. Mice in the ACLT and sham-operated groups were subjected to anaesthesia, right unilateral medial arthrotomy, patella luxation, and fat-pad elevation to visualise the ACL, at which time the surgeon was informed to transect or spare the ACL before joint closure. Uninjured and ACLR animals were anaesthetised, the latter having a single compressive load (9-12N) to posteriorly displace the femur and traumatically rupture the ACL. Animals were housed in mixed injury groups (up to 5/cage) and allowed unrestricted activity. At 1, 2, 4 and 8 weeks post-injury, mice were euthanised and joints harvested for fixation, paraffin embedding, sectioning and OA histopathology scoring (n=7/group/timepoint); or synovial tissue (en bloc fat-pad, synovial lining and joint capsule anterior to the collateral ligaments) isolation for RNA extraction and quantitative RT-PCR analysis of cytokines (IL1, IL6, TNF), inflammatory cell markers (CD11b, CD4, CD8), and enzymes implicated in OA pathophysiology (ADAMTS4, ADAMTS5, MMP3, MMP9, MMP13) (n=6/group/time point). Results: ACL injury resulted in progressive OA pathology with cartilage pathology significantly greater in ACLR compared with ACLT at 2 and 4 weeks (p<0.001), but by 8 weeks was equivalent in the two models; posterior osteochondral erosion significantly worse in ACLR than ACLT at 4 and 8 weeks (p<0.01); and osteophyte size (p<0.001) and maturity (p<0.01) greater at 1 and 2 weels in ACLR compared with ACLT. Synovitis was increased acutely in both ACL-injuries and then decreased with time, with ACLT>ACLR (p=0.003) at week-1 but similar thereafter; both still greater than uninjured joints through to week 8 (p<0.001). Sham and ACLT had similar synovitis scores until week 8 when the latter was more severe. Despite histomorphological similarities in synovitis in ACLT and ACLR, there were differences in gene expression patterns. Synovial expression of TNF, CD11b and CD8 was unchanged at any time when comparing between groups. Surgery alone (ACLT and Sham) increased synovial IL6 (week-1: ACLT p=0.02, Sham p<0.001 vs uninjured) while ACLR did not. While CD4 was also increased by surgery (week-1 and -2: ACLT p<0.01, Sham p<0.05 vs uninjured), it was also increased in ACLR versus uninjured at these times (p<0.05; Figure 1). ADAMTS5 expression was not detected in synovial tissue, and MMP9 mRNA did not differ between groups. In contrast, ADAMTS4, MMP3, and MMP13 expression were increased by surgery (ACLT/Sham) and ACLR at week-1 and -2 compared with uninjured joint, although both surgeries>ACLR (Table 1). Conclusions: While both models caused joint instability, OA trajectory and ultimate severity were greater in ACLR. In contrast, surgery induced greater histo-pathological synovitis acutely but was similar in both injuries thereafter. There was a difference in the “phenotype” of the synovial inflammation in the two injury models. In ACLT there was upregulation of IL6 not evident in ACLR but similar to Sham, suggesting this was a response to surgery and wound healing. While helper T-cell (CD4) increase was greater in ACLT and Sham, this also occurred in ACLR suggesting a role of adaptive immunity in OA after nonsurgical injury. Expression of ADAMTS4, MMP3 and MMP13 were similarly increased acutely in both injury models, suggesting synovial tissues as a source of these enzymes implicated in the structural pathology of OA. While their expression was not correlated with ultimate pathological severity they may be broad-spectrum target across varying phenotypes of post-traumatic OA. Our data suggest that synovitis severity per se was not associated with differential OA risk with ACL injury; it likely still contributes to long-term OA structural pathology.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Biological potential alterations of migratory chondrogenic progenitor cells during knee osteoarthritic progression

BackgroundAlthough increasing studies have demonstrated that chondrogenic progenitor cells (CPCs) remain present in human osteoarthritic cartilage, the biological alterations of the CPCs from the less diseased lateral tibial condyle and the more diseased medial condyle of same patient remain to be investigated.MethodsCPCs were isolated from paired grade 1–2 and grade 3–4 osteoarthritic cartilage by virtue of cell migratory capacities. The cell morphology, immunophenotype, self-renewal, multi-differentiation, and cell migration of these CPCs were evaluated. Additionally, the distributions of CD105+/CD271+ cells in OA osteochondral specimen were determined. Furthermore, a high-throughput mRNA sequencing was performed.ResultsMigratory CPCs (mCPCs) robustly outgrew from mildly collagenases-digested osteoarthritic cartilages. The mCPCs from grade 3–4 cartilages (mCPCs, grades 3–4) harbored morphological characteristics, cell proliferation, and colony formation capacity that were similar to those of the mCPCs from the grade 1–2 OA cartilages (mCPCs, grades 1–2). However, the mCPCs (grades 3–4) highly expressed CD271. In addition, the mCPCs (grades 3–4) showed enhanced osteo-adipogenic activities and decreased chondrogenic capacity. Furthermore, the mCPCs (grades 3–4) exhibited stronger cell migration in response to osteoarthritis synovial fluids. More CD105+/CD271+ cells resided in grade 3–4 articular cartilages. Moreover, the results of mRNA sequencing showed that mCPCs (grades 3–4) expressed higher migratory molecules.ConclusionsOur data suggest that more mCPCs (grades 3–4) migrate to injured articular cartilages but with enhanced osteo-adipogenic and decreased chondrogenic capacity, which might explain the pathological changes of mCPCs during the progression of OA from early to late stages. Thus, these dysfunctional mCPCs might be optional cell targets for OA therapies.

Matrix metalloproteinase-13, NF-κB p65 and interleukin-1β are associated with the severity of knee osteoarthritis.

Knee osteoarthritis (KOA) is a prevalent disease, especially in the elderly. The present study examined the expression of matrix metalloproteinase-13 (MMP-13), NF-κBp65 and interleukin (IL)-lβ in the synovial tissues of KOA patients and the role of MMP-13 and the NF-κBp65 signalling pathway in KOA pathogenesis. A total of 100 KOA patients were enrolled in our hospital from December 2015 to December 2017 and were classified into either a mild KOA group (Outerbridge grade 1 and 2) or a severe KOA group (Outerbridge grade 3 and 4). Non-OA patients were included as controls. Synovial tissues from patients in both groups were collected for detection of the mRNA and protein expression of MMP-13, NF-κBp65 and IL-lβ. Synovial tissue slices were subjected to haematoxylin and eosin staining and immunohistochemistry (SP method). Cartilage tissues were observed under a light microscope after Safranin O-fast green staining. Reverse transcription-quantitative PCR and western blot analyses demonstrated that the expression of MMP-13, NF-κBp65 and IL-lβ in the mild and severe groups were substantially upregulated compared with the control group (all P<0.05). A positive correlation between MMP-13 and NF-κBp65 expression in the KOA synovial tissues was identified (P<0.05). Immunohistochemistry revealed that the expression of MMP-13 and NF-κBp65 was related to the severity of KOA (MMP-13: severe, 92.54%; moderate, 76.52%; control: 32.14%; and NF-κBp65: severe, 85.56%; moderate, 48.12%; control: 28.32%). This evidence indicated that the severity of KOA was related to MMP-13 and NF-κBp65 expression. The NF-κB signalling pathway may be activated during OA progression, which could upregulate the expression of MMP-13 and IL-1β and accelerate the deterioration of articular cartilage.

Two-year clinical results of a novel load redistribution device for the treatment of medial knee OA.

A potential method to relieve the pain from medial osteoarthritis of the knee is to offload the medial compartment. The Latella™ Knee Implant is a novel device designed to offload the medial compartment. The objective of the Cotera-1 study was to evaluate the preliminary safety and feasibility of the Latella implant to treat patients with medial OA of the knee, by a 2-year follow-up of a prospective multicenter feasibility study (Cotera-1) performed in the Netherlands and UK METHODS: In this first-in-man study, 11 participants received the Latella implant and were followed for 2years, documenting physician assessment, Patient-Reported Outcome (PRO) scoring (KOOS, IKDC, Kujala, SF-36); Patient Global Assessment (PGA), radiographic analysis and MRI analysis, complications, reoperation rate and hip-knee-ankle axis. The Latella Knee Implant system proved to be well tolerated and demonstrated a low-risk safety profile up to 24months post-treatment. A responder analysis was performed of the subjects who still had the Latella implanted at 24-month time point (n = 9). Based on a MCID of eight for KOOS pain sub-scale, 78% of the subjects at the 24month time point would be considered as responders. Similarly, based on improvement in the medial knee pain compared to baseline using the NRS scale of 1-10, 89% of the subjects at the 24-month time point would be considered as responders. Two patients were revised during follow-up: one for arthrofibrosis and one converted to TKA for progression of OA. The early clinical experience with the Latella Knee Implant in this pilot feasibility study has been encouraging. It appears to be a safe implant with possible effect on medial OA. Additional studies need to be performed to assess the safety and efficacy of the procedure in a larger patient population. II.

Statin use and risk of joint replacement due to osteoarthritis and rheumatoid arthritis: a propensity-score matched longitudinal cohort study.

Statins are reported to have a potential benefit on progression of OA and on disease activity in RA, but existing evidence is conflicting. Our objective was to examine whether statins associate with reduction in the risk for joint replacement due to OA and RA. This was a propensity score-matched cohort study. Electronic health records from the UK Clinical Practice Research Datalink were used. We selected people prescribed statins and people never prescribed statins. Each statin user was matched to a non-user by age, gender, practice and propensity score for statin prescription. The main outcome measures were knee or hip joint replacement overall, and specifically because of OA or RA. The association between statins and risk of joint replacement was assessed using Cox proportional hazard regression. Statin exposure was categorized according to the potency of reducing low-density lipoprotein as low (21-28%), medium (32-38%) or high (42-55%) intensity. A total of 178467 statin users were matched with 178467 non-users by age, gender, practice and propensity score. Overall, statin was not associated with reduced risk of knee or hip replacement (hazard ratio 0.99, 95% CI: 0.97, 1.03), unless prescribed at high strength (0.86, 0.75-0.98). The reduced risk was only observed for joint replacement due to RA (0.77, 0.63-0.94) but not OA (0.97, 0.94-1.01). Statins at high intensity may reduce the risk of hip or knee replacement. This effect may be RA specific. Further studies to investigate mechanisms of risk reduction and the impact in people with RA are warranted.

Meniscectomy-induced osteoarthritis in the sheep model for the investigation of therapeutic strategies: a systematic review.

One of the major risk factors for OA is meniscectomy (Mx) that causes a rapid and progressive OA. Mx has been employed in various animal models, especially in large ones, to study preclinical safety and strategy effectiveness to counteract OA. The aim of the present study is to review in vivo studies, performed in sheep and published in the last tenyears. The search strategy was performed in three websites: www.scopus.com, www.pubmed.com, and www.webofknowledge.com, using "Meniscectomy and osteoarthritis in sheep" keywords. The 25 included studies performed unilateral total medial Mx (MMx), unilateral partial MMx, bilateral MMx, unilateral total lateral Mx (LMx), unilateral partial LMx, and bilateral LMx and MMx combined with anterior cruciate ligament transaction. The most frequently performed is the unilateral total MMx that increases changes in cartilage and subchondral bone more than the other techniques. Gross evaluations, histology, radiography, and biochemical tests are used to assess the degree of OA. The most widely tested treatments are related to scaffolds with or without mesenchymal stem cells. OA therapeutic strategies require the use of large animal models due to similarities with human joint anatomy. A protocol for future in vivo studies on post-traumatic OA is clarified.

Stem-Cell Derived Exosomes for the Treatment of Osteoarthritis.

Osteoarthritis(OA) is a common degenerative orthopedic disease with multiple pathologic changes in joints affecting large populations worldwide. No treatment can reverse the progress of OA. Since exosomes were first reported in 1983, researches have been conducted to explore the mechanisms and therapeutic potential of exosomes in treating OA. Exosomes derived from Mesenchymal stem cells have attracted increasing attention in tackling the disease. This article summarizes the current advances and challenges in exosomes for OA, which may providea reference for further research.

Clinical significance of bone marrow edema in the late stages of osteoarthritis

The use of magnetic resonance imaging (MRI) for osteoarthritis made it possible to simultaneously detail the state of cartilage, subchondral bone, menisci, ligaments, and synovial membrane. In some studies, a correlation was found between bone marrow edema (BME) and the intensity of the pain syndrome, the progression of OA and the risk of total knee replacement. In other studies, these data were not confirmed. It has been suggested that BME in OA, leading to debilitating pain, is not associated with trauma and is determined by an increase in extracellular fluid. Analysis of MRI images of 80 patients with 1-3 stages of knee osteoarthritis revealed a statistically significant relationship between the presence of bone marrow edema and the thickness of the cartilage of the femur and tibia, rupture and degradation of the medial menisci, the presence of Baker cysts and thickening of the synovial membrane. No reliable relationship was found with the presence and severity of synovitis. A review of data on the effect of various methods of conservative therapy on bone marrow edema in osteoarthritis is presented. The effect of anti-osteoporotic drugs, prostacyclin, Pentosan polysulfate sodium chondroitin sulfate is considered. Thus, OKM is of interest both in terms of the pathogenesis of OA and as an indicator of the effectiveness of the treatment of OA. Our data demonstrate a high incidence of OKM in the late stages of OA. The effect of pharmacological therapies on OKM requires further study.

Macrophages regulate the progression of osteoarthritis

OA is now well accepted as a low-grade inflammatory disease affecting the whole joint. In addition to mechanical loading, inflammation (particularly synovitis), contributes significantly to OA. Synovial macrophages act as immune cells and are of critical importance in the symptomology and structural progression of OA. Activated macrophages are regulated by mTOR, NF-κB, JNK, PI3K/Akt and other signaling pathways, and are polarized into either M1 or M2 subtypes in OA synovial tissues, synovial fluid, and peripheral blood. The activation state and the M1/M2 ratio is highly associated with OA severity. Aside from autocrine interactions, paracrine interactions between macrophages and chondrocytes play a vital role in the initiation and development of OA by secreting inflammatory cytokines, growth factors, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs), which lead to subsequent cartilage degradation and destruction. Treatments targeting synovial macrophages relieve pain, and protect from synovitis, cartilage damage, and osteophyte formation during OA development. Macrophage reprogramming of transformation from the M1 to M2 subtype, more than a decrease in the quantity of activated macrophages, appears to be an effective treatment option for OA. This review provides a broad understanding of the contributions of polarized macrophages to joint health and disease. Multifunctional agents with immunomodulatory effects on macrophage reprogramming can skew the inflammatory microenvironment towards a pro-chondrogenic atmosphere, and are thus, potential therapeutic options for the treatment of OA and other immune diseases.

Expression of MiR-140 and MiR-199 in Synovia and its Correlation with the Progression of Knee Osteoarthritis.

BackgroundThe aim of this study was to explore the expression of miR-140 and miR-199 in synovia of patients with knee osteoarthritis (KOA) and its correlation with the progression of this disease. We used the Kellgren and Lawrence grading (KLG) system.Material/MethodsThere were 110 patients with early (KLG <2), middle (KLG=2) and late (KLG >2) stage KOA and 60 healthy individuals (control) included in this study.ResultsThe relative expression levels of miR-140 (1.07±0.091) and miR-199 (1.03±0.110) in synovia of the control group were higher than those of KOA groups (0.511±0.130, 0.298±0.168) and the difference exhibited statistical significance (P<0.01). Expression of miR-140 in the middle and the late stage KOA groups (0.322±0.118 and 0.110±0.088 respectively) were 58.80% and 81.29% lower, respectively, compared to the early stage KOA group (0.588±0.172), which was significant (P<0.05). Expression of miR-199 in the middle and the late stage KOA groups (0.210±0.124 and 0.056±0.068 respectively) were 39.41% (P<0.05) and 83.72% (P<0.01) respectively lower than that in the early KOA group (0.344±0.147). The severity of OA was significantly negatively correlated with the expressions of miR-140 and miR-199 (r=−0.859, P<0.05; r=−0.724, P<0.001 respectively). Matrix metalloproteinase (MMP)-3 levels of the early stage, middle stage and late stage KOA groups were 1.320±0.118, 1.488±0.210, and 1.955±0.023 respectively; and IL-1β mRNA was 1.401±0.204, 1.522±0.210, and 1.889±0.217 respectively, which were obviously higher than those in the control group (1.020±0.085), (P<0.05).ConclusionsExpression levels of miR-140 and miR-199 in synovia might act as an early diagnostic marker for KOA. These expression levels might also act as indicators of OA progression to some extent.

Statistical shape modelling provides a responsive measure of morphological change in knee osteoarthritis over 12 months.

Responsive biomarkers are needed to assess the progression of OA and their lack has hampered previous clinical trials. Statistical shape modelling (SSM) from radiographic images identifies those at greatest risk of fast-progression or joint replacement, but its sensitivity to change has not previously been measured. This study evaluates the responsiveness of SSM in knee OA in a 12-month observational study. A total of 109 people were recruited who had undergone knee radiographs in the previous 12 months, and were grouped based on severity of radiographic OA (Kellgren-Lawrence grading). An SSM was built from three dual-energy X-ray absorptiometry scans at 6-month intervals. Change-over-time and OA were assessed using generalized estimating equations, standardized response means (SRM) and reliable change indices. Mode 1 showed typical features of radiographic OA and had a strong link with Kellgren-Lawrence grading but did not change significantly during the study. Mode 3 showed asymmetrical changes consistent with medial cartilage loss, osteophytes and joint malalignment, and was responsive to change, with a 12-month SRM of 0.63. The greatest change was observed in the moderate radiographic OA group (SRM 0.92) compared with the controls (SRM 0.21), and the reliable change index identified 14% of this group whose progression was clinically significant. Shape changes linked the progression of osteophytosis with increasing malalignment within the joint. Modelling of the whole joint enabled quantification of change beyond the point where bone-to-bone contact has been made. The knee SSM is, therefore, a responsive biomarker for radiographic change in knees over 12 months.

FEATURES OF SOME ANTHROPOMETRIC INDICES AND INDICES OF INSULIN RESISTANCE IN PATIENTS WITH NON-ALCOHOLIC STEATOHEPATITIS ON THE BACKGROUND OF OBESITY AND OSTEOARTHRITIS

The aim: To estimate the diagnostic and predictive value of anthropometric indices indicating obesity and glycemic parameters in the progression of NASH due to comorbidity with OA and OB. Materials and methods: 90 patients were examined and distributed into three groups: group 1 included patients suffering from OA, grade II-III according to Kellgren and Lawrense classification, with normal body mass, group 2 -patients with NASH and obesity without OA, group 3 -patients with OA, NASH and obesity. The control group consisted of 30 healthy individuals of the corresponding age. Results: There was a correlation between lipid and carbohydrate metabolism. This fact was confirmed by the evidence that under the influence of IR there was an increase in the level of lipoproteins enriched in triglycerides, the concentration of cholesterol of low density lipoprotein and reduction in level cholesterol of high density lipoprotein, which led to the progression of the clinical course of NASH. It was established that anthropometric indices of patients with comorbid flow of NASH, OA and OB were significantly (p <0.05) higher than in experimental groups. A positive correlation was found between some anthropometric indices and the following glycemic parameters: fasting blood glucose, HOMA-IR suggested that insulin resistance contributed to the growth of glycated compounds leading not only to the progression of NASH and affect the dysfunction of chondrocytes, but also influencing destruction of subchondral bone in osteoarthritis. Conclusions: The outcomes of the study result in the necessity of studying the metabolic status in patients with a comorbid progression of NASH, OB and OA for timely correction of the revealed disorders, which will reduce the run of NAFLD.

β-Hydroxyisovalerylshikonin inhibits IL-1β-induced chondrocyte inflammation via Nrf2 and retards osteoarthritis in mice.

Osteoarthritis is a chronic degenerative disease characterized by cartilage destruction. It is the fourth most disabling disease worldwide and is currently incurable. Inflammation and extracellular matrix (ECM) degradation are considered to be substantial reasons for accelerating the progression of OA. β-Hydroxyisoamylshikonin (β-HIVS) is a natural naphthoquinone compound with anti-inflammatory and antioxidant activity. However, the effect of β-HIVS on OA is still unclear. In this study, we found that β-HIVS can down-regulate the expression of NO, PEG2, IL-6, TNF-α, COX-2, and iNOS, suggesting its anti-inflammatory effects in chondrocytes; we also found that β-HIVS may down-regulate the expression of ADAMTS5 and MMP13 and up-regulate the expression of aggrecan and collagen II to inhibit the degradation of ECM. Mechanistically, β-HIVS inhibited the NFκB pathway by activating the Nrf2/HO-1 axis, thereby exerting its anti-inflammatory and inhibitory effects on ECM degradation. In vivo experiments also proved the therapeutic effects of β-HIVS on OA in mice, and Nrf2 is the target of β-HIVS. These findings indicate that β-HIVS may become a new drug for the treatment of OA.

Inhibition of Nrf2/HO-1 signaling leads to increased activation of the NLRP3 inflammasome in osteoarthritis

IntroductionOsteoarthritis (OA) is an inflammatory disease of the joints that causes progressive disability in the elderly. Reactive oxygen species (ROS) play an important role in OA development; they may activate the NLRP3 inflammasome, thereby inducing the secretion of proinflammatory IL-1β and IL-18, leading to the aggravation of the downstream inflammatory response. Nrf2 is a key transcription factor that regulates the expression of antioxidant enzymes that protect against oxidative stress and tissue damage. We aimed to explore the underlying mechanism of OA development by investigating NLRP3, ASC, Nrf2, and HO-1 expression in synovia and their regulatory networks in OA.MethodsHuman total knee replacement samples were subjected to histology and micro-CT analysis to determine the pathological changes in the cartilage and subchondral bone and to assess the expression of inflammation-related markers in the synovial tissue by immunohistochemistry (IHC), qRT-PCR, and Western blot. To investigate these pathological changes in an OA animal model, adult Sprague-Dawley rats were subjected to anterior cruciate ligament transection and medial meniscectomy. Articular cartilage and subchondral bone changes and synovial tissue were also determined by the same methods used for the human samples. Finally, SW982 cells were stimulated with lipopolysaccharide (LPS) as an in vitro inflammatory cell model. The correlation between NLRP3 and Nrf2 expression was confirmed by knocking down NLRP3 or Nrf2.ResultsCartilage destruction and subchondral bone sclerosis were found in the OA patients and OA model rats. Significantly increased expression levels of NLRP3, ASC, Nrf2, and HO-1 were found in the synovial tissue from OA patients. NLRP3, ASC, Nrf2, and HO-1 expression in the synovium was also upregulated in the OA group compared with the sham group. Furthermore, the NLRP3, Nrf2, HO-1, IL-1β, and IL-18 expression in LPS-treated SW982 cells was increased in a dose-dependent manner. As expected, the expression of NLRP3 was upregulated, and the expression of IL-1β and IL-18 was downregulated after Nrf2 silencing. However, knocking down NLRP3 did not affect the expression of Nrf2.ConclusionsROS-induced oxidative stress may be the main cause of NLRP3 inflammasome activation and subsequent release of downstream factors during OA development. Nrf2/HO-1 signaling could be a key pathway for the activation of the NLRP3 inflammasome, which may contribute to the progression of OA. Herein, we discovered a novel role of Nrf2/HO-1 signaling in the production of NLRP3, which may facilitate the prevention and treatment of OA.

Association between stages of medial compartment osteoarthritis and three-dimensional knee alignment in the supine position: A cross-sectional study

BackgroundOsteoarthritis (OA) of the knee causes changes in knee alignment. A detailed knowledge of knee alignment is needed for correct assessment of the extent of disease progression, determination of treatment strategy, and confirmation of treatment effectiveness. However, deterioration of knee alignment during progression of OA has not been adequately characterized. The aims of this study were to clarify the changes in three-dimensional static knee alignment as knee OA stage progressed and to lay a foundation for an optimal treatment strategy to prevent knee malalignment. MethodsA total of 106 knees of 81 patients ((men/women) 45/36; mean age 48.4 ± 19.9 years; body mass index (BMI) 25.7 ± 4.4 kg/m2) were enrolled in this cross-sectional study, comprising 34 (33/1) in Kellgren-Lawrence (KL) grade 0, 17 (8/9) in KL grade 1, 26 (5/21) in KL grade 2, 19 (4/15) in KL grade 3, and 10 (1/9) in KL grade 4. In all cases, computed tomography images were obtained with the subject in a reclined and relaxed position with the knee straight. Three-dimensional bone models were created from the images and knee alignment was calculated with six degrees-of-freedom. Then, 40 knees were selected consisting of 10 sex- and BMI-matched knees from each KL grade group: KL grade 1 (mean age 54.6 ± 8.4 years; BMI 23.3 ± 3.5 kg/m2), grade 2 (64.7 ± 10.9 years; 27.3 ± 3.2 kg/m2), grade 3 (69.2 ± 11.4 years; 27.1 ± 4.3 kg/m2), and grade 4 (71.9 ± 9.2 years; 27.2 ± 3.6 kg/m2). The Mann–Whitney U test with Bonferroni correction for multiple comparisons was used to analyze static alignment (α < 0.05/6). ResultsAlignment of the knee in flexion was -4.0 [95% confidence interval (CI): -6.4, -1.5] degrees, -3.4 [-8.0, 1.3] degrees, -0.1 [-3.7, 3.5] degrees, and 0.4 [-0.9, 1.6] degrees in the order of KL grade 1 to 4. There were significant differences between KL grade 1 and 4 (p = 0.0081). Anterior tibial translation was 6.6 [4.6, 8.6] mm, 5.8 [1.9, 9.7] mm, 1.0 [-2.5, 4.5] mm, and 1.3 [-2.4, 5.1] mm in the order of grade 1 to 4. There were significant differences between KL grade 1 and 4 (p = 0.0081). There were no significant differences in lateral tibial translation nor tibial rotation. ConclusionsThe severely osteoarthritic knee joint was flexed and the tibia was displaced posteriorly with respect to the femur. Preventing these changes in alignment would assist in the prevention and treatment of knee OA.

Identifying the role of ASPN and COMP genes in knee osteoarthritis development

BackgroundOsteoarthritis (OA) is a common cause of musculoskeletal disability among elders and is characterized by late-onset degeneration of articular cartilage. OA affects various joints, commonly hand, knee, and hip, with clinical features that are unique to each joint. This study was initiated to identify and evaluate the role of the ASPN and COMP genes in the development of knee OA.MethodsA case–control study was carried out involving 500 cases with knee OA (diagnosed by the American College of Rheumatology) and an equal number of healthy controls. Blood was drawn for genomic DNA isolation. PCR-RFLP and TaqMan assay methods were used to identify the SNPs. mRNA and protein expression of genes were carried out in peripheral blood lymphocytes (PBLs) by RT-PCR and Western immunoblotting. The data obtained were analyzed for the statistical significance between control and case groups.ResultsThe variant genotype of ASPN and COMP genes was found to be present at a relatively higher frequency in cases than controls. RT-PCR and immunochemical studies revealed increased mRNA and protein expression of such gene in PBLs isolated from cases of knee OA as compared to healthy control.ConclusionThe allelic alteration in ASPN and COMP genes in knee OA cases points to the role of these genes in the development of knee OA. Further, increased mRNA and protein expression of ASPN and COMP in peripheral blood samples of patients with the disease suggest that expression profile of candidate gene could be used as a biomarker for predicting the development and progression of knee OA.

Longitudinal validity of using digital hand photographs for assessing hand osteoarthritis progression over 7\u2009years in community-dwelling older adults with hand pain

BackgroundTo determine the longitudinal construct validity of assessing hand OA progression on digital photographs over 7 years compared with progression determined from radiographs, clinical features and change in symptoms.MethodsParticipants were community-dwelling older adults (≥50 years) in North Staffordshire, UK. Standardized digital hand photographs were taken at baseline and 7 years, and hand joints graded for OA severity using an established photographic atlas. Radiographic hand OA was assessed using the Kellgren and Lawrence grading system. Hand examination determined the presence of nodes, bony enlargement and deformity. Symptoms were reported in self-complete questionnaires. Radiographic and clinical progression and change in symptoms were compared to photographic progression. Differences were examined using analysis of covariance and Chi-Square tests.ResultsOf 253 individuals (61% women, mean age 63 years) the proportion with photographic progression at the joint and joint group-level was higher in individuals with radiographic or clinical progression compared to those without, although differences were not statistically significant. At the person-level, those with moderate photographic progression over 7 years had significantly higher summed radiographic and clinical scores (adjusted for baseline scores) compared to those with no or mild photographic progression. Similar findings were observed for change in symptoms, although differences were small and not statistically significant.ConclusionAssessing hand OA on photographs shows modest longitudinal construct validity over 7 years compared with change in radiographic and clinical hand OA at the person-level. Using photographs to assess overall long-term change in a person with hand OA may be a reasonable alternative when hand examinations and radiographs are not feasible.

Notch1-ADAM8 positive feed-back loop regulates the degradation of chondrogenic extracellular matrix and osteoarthritis progression

BackgroundOsteoarthritis (OA) is one of the most prevalent joint disease, and there are still no effective therapeutic agents or clinical methods for the cure of this disease to date. The degradation of cartilage extracellular matrix (ECM) is a major cause of OA.MethodIL-1β was used to induce chondrogenic degradation. Q-PCR and Western blotting were used to detect mRNA and protein level, respectively. ELISA was used to detect the secreted TNF-α and IL-6 level. Immunofluorescence was used to detect the protein level of Aggrecan, Collagen II and ki67. TUNEL and flow cytometry were used to examine cell apoptosis of chondrocytes. ChIP and luciferase assay were used to study molecular gene regulation. Osteoarthritic animal model and Safranin-O staining were used to determine the in vivo OA phenotype.ResultsThe expression of ADAM8 was up-regulated in osteoarthritic chondrocytes. Knockdown of ADAM8 suppressed the OA phenotype in the in vitro OA cell model. ADAM8 regulated OA progression through the activation of EGFR/ERK/NF-κB signaling pathway. Inhibition of Notch signaling suppressed OA phenotype in the in vitro OA cell model. Notch signaling regulated the gene expression of ADAM8 directly via Hes1. Notch1-ADAM8 positive feedback loop promoted the progression of OA in vivo.ConclusionNotch1-ADAM8 feed-back loop regulates the degradation of chondrogenic extracellular matrix and osteoarthritis progression.