Faculty Bibliography

Osteoarthritis (OA) is characterized by progressive loss of articular cartilage accompanied by the new bone formation and, often, a synovial proliferation that culminates in pain, loss of joint function, and disability. However, the cellular and molecular mechanisms of OA progression and the relative contributions of cartilage, bone, and synovium remain unclear. We recently found that the extracellular matrix (ECM) protein periostin (Postn, or osteoblast-specific factor, OSF-2) is expressed at high levels in human OA cartilage. Multiple groups have also reported elevated expression of Postn in several rodent models of OA. We have previously reported that in vitro Postn promotes collagen and proteoglycan degradation in human chondrocytes through AKT/β-catenin signaling and downstream activation of MMP-13 and ADAMTS4 expression. Here we show that Postn induces collagen and proteoglycan degradation in cartilage by signaling through discoidin domain receptor-1 (DDR1), a receptor tyrosine kinase. The genetic deficiency or pharmacological inhibition of DDR1 in mouse chondrocytes blocks Postn-induced MMP-13 expression. These data show that Postn is signaling though DDR1 is mechanistically involved in OA pathophysiology. Specific inhibitors of DDR1 may provide therapeutic opportunities to treat OA.

Background/Purpose : Psoriatic arthritis (PsA) is a heterogenous inflammatory disease affecting skin, joints, and other domains. While psychiatric diseases (i.e., depression and anxiety) are known comorbidities, little is known about their impact on disease severity and patient reported outcomes (PROs). The objective of this study was to characterize the prevalence of psychiatric comorbidities in an academic combined psoriasis-psoriatic arthritis center and determine their impact on PsA clinical and patient derived outcomes. Methods : Consecutive adult patients meeting CASPAR criteria for PsA (n=436) were prospectively recruited at the NYU Psoriatic Arthritis Center. All data was collected from clinical visits utilizing a standardized EPIC template. Depression was defined by established diagnosis and/or use of anti-depressant medications. Objective measures of disease severity included swollen and tender joint counts (SJC/TJC) and PROs including RAPID3 scores. Data was analyzed using statistical software R. Results : Our cohort was comprised of 436 patients: 54% male, mean age of 47 years, and mostly Caucasians (74.1%). Within our population, 19.5% had depression, 15.6% had anxiety, and 4.8% had ADHD (Table 1). Of those with depression, 71% were on anti-depressive medication. At the initial visit, patients with PsA and depression were more likely to be on medication(s) for PsA (80% vs 65%, p=.01) and had a trend towards higher rates of biologic use (47.5% vs 40.4%, p=.126). Those with depression had a similar TJC to their non-depressed counterparts, but had a trend towards fewer swollen joints and concomitant higher RAPID3 scores (Table 2). When analyzing repeated outcome measures over subsequent visits, individuals with depression were similarly more likely to have a higher TJC, a lower SJC, and a higher RAPID3 score (although only RAPID3 was found to be statistically significant, p=.004). Importantly, these findings persisted when analyzing participants that were matched with propensity scores to adjust for age, sex, comorbidities, and medication use. In addition to joint activity, psoriasis activity measured by body surface area (BSA) was lower in those who were depressed (1.4% vs 3.03%, p=.001) and these differences were maintained over subsequent visits. Conclusion : Our results expand on prior reports of significantly elevated rates of depression in PsA. Notably, individuals with depression were more likely to be on medication(s) for their PsA, had fewer swollen joints, and a lower BSA but, paradoxically reported higher RAPID3 scores. This discrepancy is likely a manifestation of how depression could affect the way patients experience their PsA despite apparent improvement in skin and joint symptoms. Depression should, therefore, be considered a critical comorbidity when addressing PsA care in routine visits. Further work is needed to understand whether modulation of psychiatric comorbidities can lead to improved PsA outcomes

Background/Purpose : Weight loss in obese patients can reduce knee osteoarthritis (OA) pain, even when physical therapy and intra-articular injections have failed. The impacts of either non-surgical or surgical weight loss on knee OA pain have been reported separately, but few studies have assessed them conjointly. While the decrease in mechanical load helps, the contribution of metabolic changes is less clear. We aimed to compare biomarker changes with weight loss as predictors of knee pain improvement, and consider a threshold of total weight loss necessary for these changes. Methods : Patients from the NYU Langone Weight Management program were screened for knee pain prior to bariatric surgery or the start of a medical weight loss (MWL) regimen. We excluded patients with autoimmune disease, recent malignancy, recent intra-articular knee injections, and lack of OA by Kellgren-Lawrence (KL) x-ray grading. The BMI, Knee Injury and Osteoarthritis Outcome Score (KOOS) for pain, and blood samples were obtained at baseline and 1, 3, 6 and 12 months for evaluation of pain and biomarker levels. Results : Of 140 patients screened, 81 were eligible and enrolled (82.7% female; BMI 45.2+/-9.6 kg/m2, 31-74; age 52+/-12 years, 30-80). A total of 49 patients had surgery (10 bypass, 30 sleeve, 9 LapBand) and 24 medical weight loss. 33 patients completed visits up to 6 months (2 bypass, 18 sleeve, 6 LapBand, 7 MWL). By 1 month, the surgical patients had lost much more total weight than the MWL group (9.8% vs 4.1 %, p=0.001), and realized marked pain relief (p< 0.001). By 6 months both groups had continued to lose weight, proportionately greater for surgical patients with further pain improvement. (Figure 1) Leptin levels dropped at 1 and then 6 months with both methods of weight loss. The pro-inflammatory protein IL-1Ra decreased significantly by 6 months in the bariatric patients, but increased with the medical regimen across both time points. Soluble vascular adhesion protein 1 (sVAP-1), another pro-inflammatory protein that facilitates leukocyte infiltration, decreased at both the 1 and 6 month intervals -but much more in MWL than in surgical patients. Consistent with the literature, the anti-inflammatory soluble receptor for advanced glycation endproducts (sRAGE) mirrored KOOS pain improvement only in surgical patients and stabilized after 1 month, but did not change in the MWL group. (Table 1) In a subgroup analysis, the 14 surgical patients who lost at least 10% of Figure 1. Surgical and medical outcomes for % total weight loss (TWL), knee pain and biomarkers Table 1. total weight by 1 month had significantly less pain at 6 months than the 12 who did not meet the threshold (DELTAKOOS 47.5 vs 29.9) but the biomarker levels were similar. (Figure 2) Conclusion : Surgical and medically supervised weight loss both lead to significant decreases in adiposity, but only those having bariatric surgery realize significant pain relief. The anatomical changes of surgical (vs. medical) weight loss result in different metabolic cascades given divergent biomarker trends. Bariatric patients who lose more than 10 percent of total body weight within the first month are more likely to have better pain relief by 6 months, but the biomarker changes reflect anatomic intervention -and are not dependent on the degree of surgical weight loss

Background/Purpose : About 30% of patients with skin psoriasis (PsO) develop psoriatic arthritis (PsA). The reasons for why only some progress to synovio-enthesial disease from skin involvement remains unknown. Genetic, environmental and clinical-demographic factors have been implicated, but are yet to be characterized in specialized, combined care centers. We aim to describe clinical phenotypes differentiating patients with PsO from those with PsA at a large, urban tertiary care PsO-PsA clinic. Methods : Consecutive adult patients meeting CASPAR criteria for PsA (n= 448) or with dermatologist diagnosed skin psoriasis only (n=161) were prospectively recruited at the NYU Psoriatic Arthritis Center and the NYU Psoriasis and Psoriatic Arthritis Clinic. All data was collected utilizing clinical visit notes and additional on-site questionnaires. Type of psoriasis and body surface area (BSA) was determined by dermatologists or rheumatologists specializing in psoriatic disease. Data was analyzed using statistical software SPSS using chi squared test with Yates Continuity Correction for dichotomous/categorical variables and t-test for continuous variables. Results : Patients with PsO were more likely to be older (52.7 vs. 48.9, p=.032) and have hypertension, obesity, diabetes, and history of myocardial infarction (Figure 1). Patients with PsO had a statistically higher BSA than those with PsA (5.8% vs 3.1%, p=.003). While the type of psoriasis was similar, the site of psoriasis involvement (specifically the scalp and nail) differentiated the populations (Table 1). In PsA compared to PsO, the odds ratio of scalp involvement was 2.96 (95% Confidence Interval [CI] 2.02, 4.34) and that of nail involvement was 14.66 (95% CI 8.21, 26.16). Inverse psoriasis was not different between groups. Additionally, those with PsA were much more likely to have a first degree relative (FDR) with psoriasis compared to those with cutaneous disease alone (31.9% vs. 12.0%, p=.007) (Figure 1). Conclusion : We report for the first time the comorbidities and psoriasis features of PsA and PsO populations in a large, combined center. We found that scalp involvement and any nail involvement was more prevalent in the PsA as compared to PsO. Only one previous study has identified scalp psoriasis[1] as a possible risk factor for progression, while previous studies looking at nail psoriasis reported much lower odds ratios[1,2]. Patients with PsA also demonstrated a higher number of FDRs with skin psoriasis, reinforcing the notion of strong heritability in PsA. The identification of risk factors for progression is of critical importance to study natural history of psoriatic disease and to inform the adequate design of prevention trials in psoriasis patients who have enriched features associated with future transition to synovio-enthesial disease

Background/Purpose : Osteoarthritis (OA) is a highly heterogeneous disease, which suggest that multiple endotypes exist. Identification and characterization of such endotypes may assist in precision medicine for identification of faster progressors whom may benefit from a given type of intervention. Recent published data have shown that SNPs in growth factors such as TGFbeta and GDF are associated with OA, which indicate that cartilage formation and repair play an important role in progression of OA. The aim was to determine whether a biomarker of type II collagen formation measured in serum, as a potential surrogate measure of cartilage formation, could predict radiographic progression in knee OA population. Subsequently, we investigated if such a proposed low cartilage formation/repair endotype was more responsive to a potential treatment of OA. Methods : hsPRO-C2, a measurement of the type II collagen pro-peptide, was measured in blood samples of two independent knee OA cohorts: 106 recruited at New York University (NYU cohort) and 147 from the phase III OA trial SMC021-2301 (clinicaltrial.gov: NCT00486434) evaluating the efficacy and safety of oral salmon calcitonin. Patients were dichotomized based on their baseline level of hsPRO-C2 and the mean difference in two-year radiographic progression (joint space narrowing (JSN)) was analyzed using ANCOVA adjusting for baseline demographics and clinical characteristics. Results : In the NYU cohort, baseline plasma hsPRO-C2 levels were negatively correlated with the progression of radiographic JSN (r = -0.26, p = 0.009). Quartile analysis demonstrated a significant difference in mean JSN from quartile 1 to 4 (0.51 mm versus -0.07 mm, p = 0.036, fig. 1). Knee OA patients with low hsPRO-C2 levels (<= 1.48 ng/mL) revealed significantly larger JSN compared to the individuals with high hsPRO-C2 levels ( > 1.48 ng/ mL) at 24 months (0.37 mm vs 0.02 mm, p = 0.042). In the SMC cohort, there was no significant treatment effect on the medial JSN over 2 years before stratification by hsPRO-C2; however, as observed in the NYU cohort, JSN was on average higher in the low hsPRO-C2 (<= 1.96 ng/mL) group compared to the high group ( > 1.96 ng/ mL). Furthermore, in the low baseline hsPRO-C2 subgroup, sCT-treated patients on average had a lower JSN compared to placebo patients (p < 0.05, fig. 2). The opposite trend was observed in patients with high baseline hsPRO-C2. Conclusion : Here we show that low levels of cartilage formation, measured by PRO-C2, were associated with radiographic progression and greater likelihood of response to a salmon calcitonin. Low PRO-C2 may provide a measure of an OA endotype with low background cartilage formation (at baseline) and higher capacity for repair when treated with a potential cartilage anabolic drug

BACKGROUND:To investigate the expression of vascular adhesion protein-1 (VAP-1) in joint tissues and serum in symptomatic knee osteoarthritis (SKOA) patients and examine whether VAP-1 levels predict increased risk of disease severity in a cross-sectional study. METHODS:Baseline VAP-1 expression and soluble VAP-1 (sVAP-1) levels were assessed in the synovium synovial fluid and in the serum in cohorts of patients with tibiofemoral medial knee OA and healthy subjects. Standardized fixed-flexion poster anterior knee radiographs scored for Kellgren-Lawrence (KL) grade (0-4) and medial joint space width (JSW). KL1/2 vs. KL3/4 scores defined early and advanced radiographic severity, respectively. Biochemical markers assessed in serum or synovial fluids (SF) comprised sVAP-1, interleukin 1 receptor antagonist (IL-1Ra), interleukin 6 (IL-6), soluble receptor for advanced glycation end-products (sRAGE), C-C motif chemokine ligand 2 (CCL2), C-C motif chemokine ligand 4 (CCL4), cluster of differentiation 163 (CD163), high sensitivity C-reactive protein (hsCRP), and matrix metalloproteinases (MMPs)-1,-3,-9. Associations between biomarkers and radiographic severity KL1/2 vs. KL3/4 (logistic regression controlling for covariates) and pain (Spearman correlation) were evaluated. RESULTS:Elevated levels of sVAP-1 observed in OA synovial fluid and VAP-1 expression in synovium based on immunohistochemical, microarray, and real-time quantitative polymerase chain reaction (qRT-PCR) analyses. However, serum sVAP-1 levels in OA patients were lower than in controls and inversely correlated with pain and inflammation markers (hsCRP and soluble RAGE). Soluble VAP-1 levels in serum were also lower in radiographically advanced (KL3/4) compared with early KL1/2 knee SKOA patients. CONCLUSION/CONCLUSIONS:Local (synovial fluid) semicarbazide-sensitive amine oxidase (SSAO)/sVAP-1 levels were elevated in OA and correlated with radiographic severity. However, systemic (serum) sVAP-1 levels were lower in SKOA patients than normal and inversely correlated with pain and inflammation markers. Serum sVAP-1 levels were higher in early (KL1/2) compared with advanced (KL3/4) SKOA patients.

OBJECTIVE:Phenotypic changes of chondrocytes toward hypertrophy might be fundamental in the pathogenesis of OA, of which type X collagen (Col10) is a well-known marker. The purpose was to develop a specific immunoassay for blood quantification of a newly identified neo-epitope of type X collagen to assess its diagnostic value for radiographic knee osteoarthritis (OA). METHODS:A neo-epitope of Col10 was identified in urine samples from OA patients. A monoclonal antibody against the neo-epitope was produced in Balb/C mice. The enzyme responsible for the cleavage was identified. Immunohistochemical detection of this neo-epitope was performed on human OA cartilage. An immunoassay (Col10neo) was developed and quantified in two clinical studies: the C4Pain-003 and the NYU OA progression study. ROC curve analysis was carried out to evaluate the discriminative power of Col10neo between OA and RA. RESULTS:A neo-epitope specific mAb was produced. The Cathepsin K-generated neo-epitope was localized to the pericellular matrix of chondrocytes, while its presence was extended and more prominent in superficial fibrillation in the cartilage with advanced degradation. In the C4Pain study, a higher level of Col10neo was seen in subjects with greater KL grade. The group of the highest tertile of Col10neo included more subjects with KL3-4. In the NYU study, Col10neo was statistically higher in OA than control or RA. ROC curve analysis revealed area under the curve was 0.88 (95% CI 0.81-0.94). CONCLUSION/CONCLUSIONS:Our findings indicate that Col10neo linked to hypertrophic chondrocytes could be used as a diagnostic biochemical marker for knee OA.

Purpose: The unique properties of articular cartilage are defined by quiescent, differentiated articular chondrocytes whose homeostasis is maintained through a strict balance between anabolic and catabolic processes. This balance is shifted toward catabolic activities in osteoarthritis (OA), a disease that involves all joint tissues and disrupts the structural integrity of articular cartilage. In OA, articular chondrocytes become more hypertrophic-ike, and abnormally increase not only extracellular matrix (ECM) production but also the expression of ECM-degrading enzymes. While chondrocyte hypertrophy is indispensable for endochondral bone formation, in OA it mediates detrimental changes that lead to cartilage destruction. Our previous work established that translational control of gene expression is critical for dedifferentiation of articular chondrocytes in OA. We showed that fine-tuned control of protein synthesis by translational repressor 4E-BP (eIF4E-Binding Protein) is required for proper chondrocyte homeostasis. By binding to the m7-GTP cap-binding protein eIF4E, 4E-BP inhibits cap-dependent mRNA translation by restricting the incorporation of eIF4E into a multi-subunit initiation factor called eIF4F, which is needed to recruit 40S ribosomes to mRNA. We hypothesized that proper translational control is crucial for maintaining healthy cartilage phenotype. We therefore investigated expression of which genes is controlled (completely or partially) at the translational level. Method(s): To identify the pool of mRNAs that are translationally control in OA cartilage we first compared translation efficiencies of mRNAs by analyzing polysome profiles of rat articular chondrocytes (RAC) untreated and treated with Interleukin 1beta (IL-1beta). Expression of several translationally regulated mRNAs was then compared to their expression in human and rodent OA cartilage. Additionally, the eIF4F inhibitor was used in vivo to determine if restriction of eIF4F activity affects OA progression in ACLT rat model. Result(s): We identified 617 mRNAs that are translationally regulated by IL-1beta. One of them is the orphan receptor Nr4a1, whose protein but not mRNA level is significantly increased in OA cartilage in vivo, highlighting the exceptional potential of our approach for discovering new possible targets in OA cartilage. Modulating Nr4a1 expression in IL-1beta-treated articular chondrocytes effects expression of MMP13, the metalloproteinase that has a predominant role in OA. Intra-articular injection of 4E1RCat, an inhibitor of cap-dependent translation not only precludes Fn and Nr4a upregulation in a rodent OA model, but also significantly delays cartilage degeneration in the ACLT rat model. Conclusion(s): We identified 617 mRNAs that are translationally regulated by IL-1beta. One of them is the orphan receptor Nr4a1, whose protein but not mRNA level is significantly increased in OA cartilage in vivo, highlighting the exceptional potential of our approach for discovering new possible targets in OA cartilage. Modulating Nr4a1 expression in IL-1beta-treated articular chondrocytes effects expression of MMP13, the metalloproteinase that has a predominant role in OA. Intra-articular injection of 4E1RCat, an inhibitor of cap-dependent translation not only precludes Fn and Nr4a upregulation in a rodent OA model, but also significantly delays cartilage degeneration in the ACLT rat model.

Background/Purpose: Psoriatic Arthritis (PsA) affects up to 30% patients with psoriasis and is characterized by wide spread synovio-entheseal inflammation. Physiologically, the human gut microbiota metabolizes dietary fiber into shortchain fatty acids (FA)- which exert anti-inflammatory effects by increasing activity of regulatory T cells (Tregs).Moreover, we have previously shown decreased abundance of Akkermansia and Ruminococcus and concomitant decrease in mediumchain FA (MCFA) levels in stool of PsA patients. We therefore hypothesized that FA supplementation may have favorable effects on gut microbiome and lead to increase in tolerance, potentially serving as therapeutic target in psoriatic disease.
Method(s): Wild type (WT)animals were fed SCFA-rich diet for 14 days followed by 16S rRNA sequencing and microbiota analysis of pellet specimens.We then evaluated effects ofMCFA-rich diet in healthy subjects. Peripheral blood and stool samples were collected at days 0, 7 and 14 for 16s rRNA sequencing and FACS. Finally, we conducted a small, prospective, proof-ofprinciple study in new-onset, drug-naive psoriatic disease patients (with or without PsA). Each participant received MCFA (1 gm 4 times a day for 6 weeks). Clinical history was obtained at baseline. Skin and joint exam were performed at baseline and follow up. Serum and stool samples were collected at baseline, weeks 3, and 6 for 16S rRNA sequencing and FACS, respectively. Wilcoxon signed-rank test was used to compare differences in Tregs before and after MCFA-rich administration.
Result(s): SCFA rich diet in WT mice led to statistically significant perturbations in gut bacterial composition 14 days into intervention, with a dramatic increase in commensals (Fig 1A; p<0.001), most notably in Akkermansia(Fig 1B). MCFA administration to healthy subjects (n=7) also led to significant changes in community structure (Fig 2A; p=0.03) and associated increases in circulating Treg cells (Fig 2B; p<0.001). These findings were also observed in psoriatic disease patients (n=4) showing a significant alteration in specific taxa, including Actinobacteria (Fig 2 C; p<0.05) and Mollicutes (p=0.09) and concomitant increase in circulatory Treg cells (Fig 2D)
Conclusion(s): In both health and psoriatic disease, MCFA supplementation is associated with distinct changes in human gut microbiota composition and peripheral Treg cells. These findings rationalize the need for a larger placebo controlled, prospective trial to study the effects of MCFA in patients with psoriasis and PsA as a potential therapy alone or in combination with DMARDs. (Figure Presented)

Background/Purpose: To investigate the expression of vascular adhesion protein -1 (VAP-1) in joint tissues and serum in knee osteoarthritis (OA) patients and examine whether VAP-1 levels predict increased risk of disease severity or progression of knee OA.
Method(s): Baseline serum and synovial fluid VAP-1/semicarbazide-sensitive amine oxidase (SSAO) levels were assessed in cohorts of patients with tibiofemoral medial knee OA and healthy subjects. Standardized fixed-flexion posteroanterior knee radiographs were scored for Kellgren Lawrence (KL) grade (0-4) and medial joint space width (JSW) at the mid-portion of the joint space. Radiographic severity was defined by KL2/3 vs. KL4. Biochemical markers assessed comprised VAP-1/ SSAO, IL-1Ra, IL-6, sRAGE, CCL2, CCL4, CD163, hsCRP and MMPs-1,-3,-9. Associations between biomarkers and radiographic severity (logistic regression controlling for covariates) and pain (Spearman correlation) were evaluated.
Result(s): VAP-1 was locally overexpressed at least 2 fold in the OA synovium based on immunohistochemical, microarray and qRT-PCR analyses compared to controls. Synovial fluid SSAO levels was also significantly higher in OA (107.94+41.42) compared to normals (38.12 + 22.98 ng/ml; p=0.0001) and inversely associated with radiographic severity. We observed a positive correlation with the levels of SSAO in the synovial fluid and serum of OA patients (r=0.47; p=0.014). However, serum SSAO levels in OA patients were lower than in controls, and inversely correlated with pain and inflammation markers (CRP and soluble RAGE). Serum SSAO levels were also lower in radiographically severe (KL4) OA patients compared to KL2/3. Serum SSAO did not correlate with other markers of inflammation or radiographic joint space narrowing (JSN) over 24 months.
Conclusion(s): Synovial fluid VAP-1/SSAO levels were elevated in OA and correlate with radiographic severity. However, serum or circulating SSAO levels are lower in OA patients and inversely correlate with pain and inflammation. Serum VAP-1 levels could identify patients at increased risk for knee radiographic severity