Faculty Bibliography

Background/Purpose: Osteoarthritis (OA) is a disease characterized by pain and tissue destruction, in some cases concomitant with inflammation. The link between pain and tissue destruction is yet unknown, and there is a lack objective quantifiable parameters. Collagens are the main structural proteins of the joint extracellular matrix. The degradation of especially type I (connective tissue), II (cartilage), III (synovium) and IV (basement membrane) collagens have been shown to be elevated in OA. So we investigated whether biomarkers reflecting collagen degradation were associated with knee OA representing with different pain and inflammatory phenotypes. Methods: 111 knee OA patients, 62% women, from NYUHJD progression cohort study with varying degree of OA were included: mean (SD) age, 62 (10); mean(SD) BMI, 27(4); NSAID users, 23%; radiographic OA (KL>2) 68%; and bilateral knee OA; 87%. Pain was assessed by VASpain and WOMAC at baseline (BL) at a 2- year follow-up (FU) visit. Median (IQR) were 39 (13-69) and 37 (13-52) for BL VASpain and WOMACpain. 4 BL serum biomarkers of type I, II, III and IV collagen degradation (C1M, C2M, C3M, C4M), and the 2 inflammatory biomarkers CRPM and hsCRP, were assessed. Data were log2 transformed. Associations between BL biomarkers, BL pain and change (CHG) pain scores were assessed by multivariate linear model including gender, age, BMI, KLsignalknee, bilateral knee OA and NSAID use. Patients with cont. mild/moderate pain had a BL VASpain<54 and FU VASpain<30, cont. moderate/severe pain had VASpain>30 at baseline and FU, and transitional severe pain had either VASpain-BL<30 and VASpain-FU>54 or VASpain-BL>54 and VASpain-FU<30 (ref). Patients with; low biochemical disease activity index (bDAI) low in CRPM (<12nM) moderate bDAI were high in CRPM but low in hsCRP (<5), and high bDAI (flare) were high in CRPM and hsCRP. Results: BL association between pain and biomarkers C2M (beta -17.9, p<0.0001) and KLsignalknee (beta -5.4, p=0.0031) were significantly associated with WOMAC pain. C2M (beta -12.4, p=0.0033), C3M (beta -19.9, p=0.059), age (beta -0.84, p<0.0018), KLsignalknee (beta 8.9, p=0.0021) and bilateral knee OA (beta -12.2, p=0.087) were associated with VASpain. Association between BL biomarkers and CHG pain C2M (beta 13.3, p=0.0016), age (beta 0.5, p=0.029) and bilateral OA (beta -12.0, p=0.043) were significantly associated with delta WOMACpain. Only age, BMI and NSAID use was associated with CHG VASpain. Association between pain phenotypes and BL biomarkers Patients with cont. mild/moderate pain had significantly higher C2M compared patients with transitional severe pain (p=0.0014) and cont. moderate/severe pain (p=0.04). Biomarker, BL pain and CHG pain in patients w. inflammatory OA Patient with low bDAI had lower WOMACpain (p<0.05) and VASpain(p<0.1). C1M was higher (p<0.05) in the flare group compared to the low and moderate bDAI groups. C3M was higher (p<0.05) in the moderate bDAI group than the low DAI group. Conclusion: Different collagen degradation products are linked differentially to different phenotypes. Cartilage degradation (C2M) was consistently linked to CHG pain phenotypes, whereas it was not associated with an inflammatory phenotype. In contrast, C1M and C3M were linked to inflammatory and flared OA

Background/Purpose: Growing numbers of studies show increased expression in Osteoarthritis (OA) of inflammatory cytokines, such as IL-1beta and TNFalpha, in joint tissues and peripheral blood mononuclear (PBM) cells. The IL1 receptor antagonist (IL1RN) gene cluster region has been associated with susceptibility to knee OA, thereby further implicating inflammation in OA pathogenesis. In these studies, we examined the association of IL-1RN haplotype with the radiographic severity of symptomatic knee OA (SKOA). Methods: Genomic DNA from SKOA patients from three cohorts (NYU I, NYU-II and O

Background: Osteoarthritis (OA) is heterogeneous disease characterized by pain and tissue destruction which is in some case concomitant with inflammation. However, the link between pain and tissue destruction is yet unknown, and there is a lack objective quantifiable parameters. Collagens are the main structural proteins of the joint extracellular matrix. The degradation type I (connective tissue), II (cartilage), III (synovium) and IV (basement membrane) collagens have been shown to be elevated in joint degenerative diseases. Objectives: To investigate whether biomarkers reflecting collagen degradation were associated with symptomatic knee OA representing with different pain and inflammatory phenotypes. Methods: 111 knee OA patients, 62% women, from NYUHJD progression cohort study with varying degree of OA were included: mean (SD) age, 32 (10); mean (SD) BMI, 27 (4); NSAID users, 23%; radiographic OA (KL>2) 68%; and bilateral knee OA; 87%. Pain was assessed by VASpain and WOMAC at baseline (BL) at a 2-year follow-up (FU) visit. Median (IQR) were 39 (13-69) and 37 (13-52) for BL VASpain and WOMACpain. 4 BL serum biomarkers of type I, II, III and IV collagen degradation (C1M, C2M, C3M, C4M), and the 2 inflammatory biomarkers CRPM and hsCRP, were assessed. Data were log2 transformed. Associations between BL biomarkers, BL pain and change (CHG) pain scores were assessed by multivariate linear model including gender, age, BMI, KLsignal knee, bilateral knee OA and NSAID use. Patients with cont. mild/moderate pain had a BL VASpain<54 and FU VASpain<30, cont. moderate/severe pain had VASpain>30 at baseline and FU, and transitional severe pain had either VASpain-BL<30 and VASpain-FU>54 or VASpain-BL>54 and VASpain-FU<30 (ref). Patients with; low biochemical disease activity index (bDAI) low in CRPM (<12nM) moderate bDAI were high in CRPM but low in hsCRP (<5), and high bDAI (flare) were high in CRPM and hsCRP. Results: BL association between pain and biomarkers. C2M (beta -17.9, p<0.0001) and KLsignal knee (beta -5.4, p=0.0031) were significantly associated with WOMAC pain. C2M (beta -12.4, p=0.0033), C3M (beta -19.9, p=0.059), age (beta -0.84, p<0.0018), KLsignal knee (beta 8.9, p=0.0021) and bilateral knee OA (beta -12.2, p=0.087) were associated with VASpain. Association between BL biomarkers and CHG pain. C2M (beta 13.3, p=0.0016), age (beta 0.5, p=0.029) and bilateral OA (beta -12.0, p=0.043) were significantly associated with delta WOMACpain. Only age, BMI and NSAID use was associated with CHG VASpain. Association between pain phenotypes and BL biomarkers. Patients with cont. mild/moderate pain had significantly higher C2M compared patients with transitional severe pain (p=0.0014) and cont. moderate/severe pain (p=0.04). Biomarker, BL pain and CHG pain in patients w. inflammatory OA. Patient with low bDAI had lower WOMACpain (p<0.05) and VASpain (p<0.1). C1M was higher (p<0.05) in the flare group compared to the low and moderate bDAI groups. C3M was higher (p<0.05) in the moderate bDAI group than the low DAI group. Conclusions: Different collagen degradation products are linked differentially to different phenotypes. Cartilage degradation (C2M) was consistently linked to pain CHG and phenotypes, whereas it was not associated with an inflammatory phenotype. In contrast, C1M and C3M were linked to inflammatory OA and flared OA

The disabling and painful disease osteoarthritis (OA) is the most common form of arthritis. Strong evidence suggests that a subpopulation of OA patients has a form of OA driven by inflammation. Consequently, understanding when inflammation is the driver of disease progression and which OA patients might benefit from anti-inflammatory treatment is a topic of intense research in the OA field. We have reviewed the current literature on OA, with an emphasis on inflammation in OA, biochemical markers of structural damage, and anti-inflammatory treatments for OA. The literature suggests that the OA patient population is diverse, consisting of several subpopulations, including one associated with inflammation. This inflammatory subpopulation may be identified by a combination of novel serological inflammatory biomarkers. Preliminary evidence from small clinical studies suggests that this subpopulation may benefit from anti-inflammatory treatment currently reserved for other inflammatory arthritides.

BACKGROUND: During osteoarthritis and following surgical procedures, the environment of the knee is rich in proinflammatory cytokines such as IL-1. Introduction of tissue-engineered cartilage constructs to a chemically harsh milieu may limit the functionality of the implanted tissue over long periods. A chemical preconditioning scheme (application of low doses of IL-1) was tested as a method to prepare developing engineered tissue to withstand exposure to a higher concentration of the cytokine, known to elicit proteolysis as well as rapid degeneration of cartilage. METHODS: Using an established juvenile bovine model system, engineered cartilage was preconditioned with low doses of IL-1alpha (0.1 ng/mL, 0.5 ng/mL, and 1.0 ng/mL) for 7 days before exposure to an insult dose (10 ng/mL). The time frame over which this protection is afforded was investigated by altering the amount of time between preconditioning and insult as well as the time following insult. To explore a potential mechanism for this protection, one set of constructs was preconditioned with CoCl2, a chemical inducer of hypoxia, before exposure to the IL-1alpha insult. Finally, we examined the translation of this preconditioning method to extend to clinically relevant adult, passaged chondrocytes from a preclinical canine model. RESULTS: Low doses of IL-1alpha (0.1 ng/mL and 0.5 ng/mL) protected against subsequent catabolic degradation by cytokine insult, preserving mechanical stiffness and biochemical composition. Regardless of amount of time between preconditioning scheme and insult, protection was afforded. In a similar manner, preconditioning with CoCl2 similarly allowed for mediation of catabolic damage by IL-1alpha. The effects of preconditioning on clinically relevant adult, passaged chondrocytes from a preclinical canine model followed the same trends with low-dose IL-1beta offering variable protection against insult. CONCLUSIONS: Chemical preconditioning schemes have the ability to protect engineered cartilage constructs from IL-1-induced catabolic degradation, offering potential modalities for therapeutic treatments.

OBJECTIVE: Pro- and anti-inflammatory mediators, such as IL-1beta and IL1Ra, are produced by joint tissues in osteoarthritis (OA), where they may contribute to pathogenesis. We examined whether inflammatory events occurring within joints are reflected in plasma of patients with symptomatic knee osteoarthritis (SKOA). DESIGN: 111 SKOA subjects with medial disease completed a 24-month prospective study of clinical and radiographic progression, with clinical assessment and specimen collection at 6-month intervals. The plasma biochemical marker IL1Ra was assessed at baseline and 18 months; other plasma biochemical markers were assessed only at 18 months, including IL-1beta, TNFalpha, VEGF, IL-6, IL-6Ralpha, IL-17A, IL-17A/F, IL-17F, CRP, sTNF-RII, and MMP-2. RESULTS: In cross-sectional studies, WOMAC (total, pain, function) and plasma IL1Ra were modestly associated with radiographic severity after adjustment for age, gender and body mass index (BMI). In addition, elevation of plasma IL1Ra predicted joint space narrowing (JSN) at 24 months. BMI did associate with progression in some but not all analyses. Causal graph analysis indicated a positive association of IL1Ra with JSN; an interaction between IL1Ra and BMI suggested either that BMI influences IL1Ra or that a hidden confounder influences both BMI and IL1Ra. Other protein biomarkers examined in this study did not associate with radiographic progression or severity. CONCLUSIONS: Plasma levels of IL1Ra were modestly associated with the severity and progression of SKOA in a causal fashion, independent of other risk factors. The findings may be useful in the search for prognostic biomarkers and development of disease-modifying OA drugs.