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Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis

Fu, Wenyu; Vasylyev, Dmytro; Bi, Yufei; Zhang, Mingshuang; Sun, Guodong; Khleborodova, Asya; Huang, Guiwu; Zhao, Libo; Zhou, Renpeng; Li, Yonggang; Liu, Shujun; Cai, Xianyi; He, Wenjun; Cui, Min; Zhao, Xiangli; Hettinghouse, Aubryanna; Good, Julia; Kim, Ellen; Strauss, Eric; Leucht, Philipp; Schwarzkopf, Ran; Guo, Edward X; Samuels, Jonathan; Hu, Wenhuo; Attur, Mukundan; Waxman, Stephen G; Liu, Chuan-Ju
Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.
PMID: 38172636
ISSN: 1476-4687
CID: 5626502

Genicular Artery Embolization for Treatment of Knee Osteoarthritis: Interim Analysis of a Prospective Pilot Trial Including Effect on Serum Osteoarthritis-Associated Biomarkers

Taslakian, Bedros; Swilling, David; Attur, Mukundan; Alaia, Erin F; Kijowski, Richard; Samuels, Jonathan; Macaulay, William; Ramos, Danibel; Liu, Shu; Morris, Elizabeth M; Hickey, Ryan
PURPOSE/OBJECTIVE:To characterize the safety, efficacy, and potential role of genicular artery embolization (GAE) as a disease-modifying treatment for symptomatic knee osteoarthritis (OA). MATERIALS AND METHODS/METHODS:This is an interim analysis of a prospective, single-arm clinical trial of patients with symptomatic knee OA who failed conservative therapy for greater than 3 months. Sixteen patients who underwent GAE using 250-μm microspheres and had at least 1 month of follow-up were included. Six patients completed the 12-month follow-up, and 10 patients remain enrolled. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was evaluated at baseline and at 1, 3, and 12 months. Serum and plasma samples were collected for biomarker analysis. The primary end point was the percentage of patients who achieved the minimal clinically important difference (MCID) for WOMAC pain score at 12 months. Baseline and follow-up outcomes were analyzed using the Wilcoxon matched-pairs signed-rank test. RESULTS:Technical success of the procedure was 100%, with no major adverse events. The MCID was achieved in 5 of the 6 (83%) patients at 12 months. The mean WOMAC pain score decreased from 8.6 ± 2.7 at baseline to 4.9 ± 2.7 (P = .001), 4.4 ± 2.8 (P < .001), and 4.7 ± 2.7 (P = .094) at 1, 3, and 12 months, respectively. There was a statistically significant decrease in nerve growth factor (NGF) levels at 12 months. The remaining 8 biomarkers showed no significant change at 12 months. CONCLUSIONS:GAE is a safe and efficacious treatment for symptomatic knee OA. Decreased NGF levels after GAE may contribute to pain reduction and slowing of cartilage degeneration.
PMID: 37640104
ISSN: 1535-7732
CID: 5611392

Pathological tissue formation and degradation biomarkers correlate with patient reported pain outcomes: an explorative study

Bay-Jensen, Anne C; Attur, Mukundan; Samuels, Jonathan; Thudium, Christian S; Abramson, Steven B; Karsdal, Morten A
BACKGROUND/UNASSIGNED:The lack of disease modifying drugs in Osteoarthritis (OA) may be attributed to the difficulty in robust response based on patient-reported outcomes (PROs) linked to drug mechanism of action. Joint tissue turnover biomarkers are associated with disease progression. A subset of patients has elevated serum levels of CRP metabolite (CRPM). This explorative study investigates the associations between PROs and joint tissue turnover markers in patients with high or low CRPM. METHODS/UNASSIGNED:Serum of 146 knee OA patients of the New York Inflammation cohort and 21 healthy donors were assessed for biomarkers of collagen degradation (C1M, C2M, C3M, C4M), formation (PRO-C1, PRO-C2, PRO-C3, PRO-C4), and CRPM. Mean (SD) age was 62.5 (10.1); BMI, 26.6 (3.6); 62% women; and, 67.6% had symptomatic OA. WOMAC pain, stiffness, function, and total were recorded at baseline and at two-year follow-up. Associations were adjusted for race, sex, age, BMI, and NSAID. RESULTS/UNASSIGNED:group. The best predictive models for improvement were found for function and total with AUCs of 0.74 (p ​< ​0.01) and 0.78 (p ​< ​0.01). The best predictive models for worsening were found for function and total with AUCs of 0.84 (p ​< ​0.01) and 0.80 (p ​< ​0.05). CONCLUSION/UNASSIGNED:We hypothesize that collagen markers are prognostic tools for segregating patient populations in clinical trials.
PMID: 37342785
ISSN: 2665-9131
CID: 5542742

Genicular artery embolization for treatment of knee osteoarthritis pain: Systematic review and meta-analysis

Taslakian, Bedros; Miller, Larry E.; Mabud, Tarub S.; Macaulay, William; Samuels, Jonathan; Attur, Mukundan; Alaia, Erin F.; Kijowski, Richard; Hickey, Ryan; Sista, Akhilesh K.
Objective: Genicular artery embolization (GAE) is a novel, minimally invasive procedure for treatment of knee osteoarthritis (OA). This meta-analysis investigated the safety and effectiveness of this procedure. Design: Outcomes of this systematic review with meta-analysis were technical success, knee pain visual analog scale (VAS; 0"“100 scale), WOMAC Total Score (0"“100 scale), retreatment rate, and adverse events. Continuous outcomes were calculated as the weighted mean difference (WMD) versus baseline. Minimal clinically important difference (MCID) and substantial clinical benefit (SCB) rates were estimated in Monte Carlo simulations. Rates of total knee replacement and repeat GAE were calculated using life-table methods. Results: In 10 groups (9 studies; 270 patients; 339 knees), GAE technical success was 99.7%. Over 12 months, the WMD ranged from −34 to −39 at each follow-up for VAS score and −28 to −34 for WOMAC Total score (all p "‹< "‹0.001). At 12 months, 78% met the MCID for VAS score; 92% met the MCID for WOMAC Total score, and 78% met the SCB for WOMAC Total score. Higher baseline knee pain severity was associated with greater improvements in knee pain. Over 2 years, 5.2% of patients underwent total knee replacement and 8.3% received repeat GAE. Adverse events were minor, with transient skin discoloration as the most common (11.6%). Conclusions: Limited evidence suggests that GAE is a safe procedure that confers improvement in knee OA symptoms at established MCID thresholds. Patients with greater knee pain severity may be more responsive to GAE.
ISSN: 2665-9131
CID: 5549022

Assessing the impact of bariatrics on osteoarthritis progression [Editorial]

Samuels, Jonathan; Attur, Mukundan
PMID: 36775136
ISSN: 1522-9653
CID: 5421162

Interleukin-1 receptor antagonist gene ( IL1RN ) variants modulate the cytokine release syndrome and mortality of SARS-CoV-2

Attur, Mukundan; Petrilli, Christopher; Adhikari, Samrachana; Iturrate, Eduardo; Li, Xiyue; Tuminello, Stephanie; Hu, Nan; Chakravarti, Aravinda; Beck, David; Abramson, Steven B
OBJECTIVE/UNASSIGNED:, the gene encoding the anti-inflammatory IL-1 receptor antagonist (IL-1Ra), on the cytokine release syndrome and mortality. METHODS/UNASSIGNED:gene were assessed for association with laboratory markers of the cytokine release syndrome (CRS) and mortality. RESULTS/UNASSIGNED:rs419598 CC SNV exhibited lower inflammatory biomarker levels, and was associated with reduced mortality compared to the CT/TT genotype in men (OR 0.49 (0.23 - 1.00); 0.052), with the most pronounced effect observed between the ages of 55-74 [5.5% vs. 18.4%, p<0.001]. CONCLUSION/UNASSIGNED:modulates the COVID-19 cytokine release syndrome via endogenous " anti-inflammatory" mechanisms. SIGNIFICANCE STATEMENT/UNASSIGNED:merits further evaluation in severe SARS-CoV-2 infection.
PMID: 36711766
CID: 5602052

The Nonproteolytic Intracellular Domain of Membrane-Type 1 Matrix Metalloproteinase Coordinately Modulates Abdominal Aortic Aneurysm and Atherosclerosis in Mice-Brief Report

Silvestro, Michele; Rivera, Cristobal F; Alebrahim, Dornazsadat; Vlahos, John; Pratama, Muhammad Yogi; Lu, Cuijie; Tang, Claudia; Harpel, Zander; Sleiman Tellaoui, Rayan; Zias, Ariadne L; Maldonado, Delphina J; Byrd, Devon; Attur, Mukundan; Mignatti, Paolo; Ramkhelawon, Bhama
BACKGROUND:MT1-MMP (membrane-type 1 matrix metalloproteinase, MMP-14) is a transmembrane-anchored protein with an extracellular proteinase domain and a cytoplasmic tail devoid of proteolytic functions but capable of mediating intracellular signaling that regulates tissue homeostasis. MT1-MMP extracellular proteolytic activity has been shown to regulate pathological remodeling in aortic aneurysm and atherosclerosis. However, the role of the nonproteolytic intracellular domain of MT1-MMP in vascular remodeling in abdominal aortic aneurysms (AAA) is unknown. METHODS:We generated a mutant mouse that harbors a point mutation (Y573D) in the MT1-MMP cytoplasmic domain that abrogates the MT1-MMP signaling function without affecting its proteolytic activity. These mice and their control wild-type littermates were subjected to experimental AAA modeled by angiotensin II infusion combined with PCSK9 (proprotein convertase subtilisin/kexin type 9) overexpression and high-cholesterol feeding. RESULTS:The mutant mice developed more severe AAA than the control mice, with concomitant generation of intraaneurysmal atherosclerotic lesions and dramatically increased macrophage infiltration and elastin degradation. Aortic lesion-associated and bone marrow-derived macrophages from the mutant mice exhibited an enhanced inflammatory state and expressed elevated levels of proinflammatory Netrin-1, a protein previously demonstrated to promote both atherosclerosis and AAA. CONCLUSIONS:Our findings show that the cytoplasmic domain of MT1-MMP safeguards from AAA and atherosclerotic plaque development through a proteolysis-independent signaling mechanism associated with Netrin-1 expression. This unexpected function of MT1-MMP unveils a novel mechanism of synchronous onset of AAA and atherogenesis and highlights its importance in the control of vascular wall homeostasis.
PMID: 36073351
ISSN: 1524-4636
CID: 5335022

Depression as a Modulator of Patient Reported, but Not Physician Observed, Outcomes in Psoriatic Arthritis [Meeting Abstract]

Haberman, R; Um, S; Catron, S; Lydon, E; Attur, M; Neimann, A; Reddy, S; Troxel, A; Adhikari, S; Scher, J
Background/Purpose: Psoriatic arthritis (PsA) is a complex immune-mediated disease. Beyond its deleterious effects in the skin and joints, PsA can lead to decreased quality of life, increased psychosocial stress, and is associated with high levels of depression and anxiety. However, little is known about the effects of mental health on disease activity and severity. This may be especially important in PsA where up to half of patients have residual symptoms (i.e., pain, fatigue) despite effective immunomodulatory therapies. The objective of this study was to characterize the prevalence of psychiatric comorbidities and their impact on PsA outcomes in an urban, academic, combined clinic setting.
Method(s): Consecutive adult patients meeting CASPAR criteria (n=537) were prospectively recruited at the NYU Psoriatic Arthritis Center and followed for up to 2 years. All data was obtained from clinical visits using a standardized EPIC template. Depression was defined as patient-reported depression and/or use of anti-depressant medications.
Result(s): The cohort was 53% male, mostly Caucasian (79.7%) and had an average age of 49 years. Within our population, 23% had depression, 18% anxiety, and 4% ADHD (Table 1). At the initial visit, patients with depression were more likely to be female, older, and have concomitant anxiety compared to those without depression. Moreover, compared to their nondepressed counterparts, patients with depression had similar swollen joint counts (SJCs), tender joint counts (TJCs) and RAPID3 scores, as well as a lower percent body surface area (BSA). However, at the subsequent timepoints, while other outcomes remained similar between the groups, patients with depression had a higher TJC (Figure 1). When adjusting for age, sex, race, medication use, and comorbidities, the rate ratio (RR) of TJC in patients with depression vs. without depression was 1.23 (95%CI 0.78, 1.94, p=0.79) at baseline (Figure 2). This ratio was even higher at year 1 (RR 1.47, 95%CI 0.91, 2.35, p=0.19) and year 2 (RR 1.75, 95%CI 0.97, 3.14, p=0.07), nearing significance. In the adjusted models for SJC, BSA, and RAPID3, this pattern was not seen.
Conclusion(s): High rates of depression and anxiety in this cohort expand upon previously reported data. While most patients improve over time, TJC is significantly higher in those who carry a diagnosis of depression whereas SJC and BSA are similar in patients with and without depression. This may reflect differences in how patients with depression perceive their disease and may lead to difficulty in achieving low disease activity/remission by composite score measures. Therefore, addressing depression, along with inflammatory symptoms, should be considered, especially in those with residual pain. Further work is needed to understand if intervening on depression could help improve PsA outcomes
ISSN: 2326-5205
CID: 5512932

Role of Intestinal Dysbiosis and Nutrition in Rheumatoid Arthritis

Attur, Malavikalakshmi; Scher, Jose U; Abramson, Steven B; Attur, Mukundan
Rheumatoid arthritis is a chronic systemic immune-mediated disease caused by genetic and environmental factors. It is often characterized by the generation of autoantibodies that lead to synovial inflammation and eventual multi-joint destruction. A growing number of studies have shown significant differences in the gut microbiota composition of rheumatoid arthritis (RA) patients compared to healthy controls. Environmental factors, and changes in diet and nutrition are thought to play a role in developing this dysbiosis. This review aims to summarize the current knowledge of intestinal dysbiosis, the role of nutritional factors, and its implications in the pathogenesis of rheumatoid arthritis and autoimmunity. The future direction focuses on developing microbiome manipulation therapeutics for RA disease management.
PMID: 35954278
ISSN: 2073-4409
CID: 5287212

Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19

Nln, Ilona; Fernandez-Ruiz, Ruth; Muskardin, Theresa L Wampler; Paredes, Jacqueline L; Blazer, Ashira D; Tuminello, Stephanie; Attur, Mukundan; Iturrate, Eduardo; Petrilli, Christopher M; Abramson, Steven B; Chakravarti, Aravinda; Niewold, Timothy B
Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity. BACKGROUND: We find that a number of IFN pathway lupus risk alleles significantly impact mortality following COVID-19 infection. These data support the idea that type I IFN pathway risk alleles for autoimmune disease may persist in high frequency in modern human populations due to a benefit in our defense against viral infections. TRANSLATIONAL SIGNIFICANCE: We develop multivariate prediction models which combine genetics and known biomarkers of severity to result in greatly improved prediction of mortality in acute COVID-19. The specific associated alleles provide some clues about key points in our defense against COVID-19.
PMID: 35114420
ISSN: 1878-1810
CID: 5153812