Session Information
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose:
Paraoxonase 1 (PON1) is an HDL-associated protein, which hydrolyzes biologically active oxidized phospholipids and prevents oxidation of lipids in LDL and HDL. Increased lipid peroxidation and oxidized LDL have been implicated in the pathogenesis of rheumatoid arthritis (RA), and we previously reported low PON1 activity in active RA patients. The current work evaluated the effects of PON1 gene overexpression in the collagen antibody induced arthritis (CAIA) and the K/BxN serum transfer induced arthritis (STIA) models of RA.
Methods:
Mice homozygous for the PON1 human transgene [PON1Tg] and wild type littermate control mice [WT] were injected intraperitoneally (n = 10 per group) with either 5mg of collagen antibody cocktail (Chondrex) on day 0, and 50ug of LPS on day 3 (CAIA), or 200ul of pooled K/BxN serum on days 0 and 2 (STIA). Arthritis activity was assessed using caliper measurements of hind limbs and clinical scores 3 times weekly until sacrifice at 2 weeks. PON1 activity was assessed using paraoxon (paraoxonase), dihydrocumarin (lactonase), and phenylacetate (arylesterase) as substrates (A&R 2013; 65: 2765). Lipids were assessed by standard assays, and a luminex cytokine/chemokine panel analysis was performed for STIA group of mice.
Results:
PON1Tg mice had significantly lower arthritis activity compared to WT mice in both CAIA and STIA models (Table). Arthritis activity was more severe in STIA. PON1 activity was strongly correlated with arthritis activity using all 3 assays of PON1 function (r values= -0.5 to -0.7; all p values<0.05); higher PON1 activity was associated with lower arthritis activity by joint scores. WT mice had significant increases in triglycerides (TG) and significant decreases in both total cholesterol (TC) and unesterified cholesterol (UC) post arthritis induction. In contrast, PON1Tg mice had no significant changes in TG, TC, or UC, but had significant increases in HDL cholesterol post arthritis induction in STIA. A trend was noted for lower serum IL-6 concentrations post arthritis in the PON1Tg mice (11±6 pg/ml) compared to WT mice (15±7 pg/ml), however no significant correlations of serum cytokine/chemokine levels with arthritis activity were noted.
Conclusion:
Overexpression of the human PON1 transgene in two mouse models of RA was associated with reduction of inflammatory arthritis activity, which correlated strongly with serum PON1 activity. Further investigation of mechanisms behind these findings is warranted to evaluate potentially novel lipid pathways for treatment of RA.
|
PON1Tg |
WT |
|
|
CAIA Model |
||
|
PON1 activity [Pre] (nmoles/minute/ml) |
268 ± 66* |
121 ± 38 |
|
Age (months) |
8.6 ± 0.6 |
8.7 ± 0.6 |
|
Sex (% female) |
50 |
50 |
|
Final total joint score |
3.7 ± 1.8* |
5.8 ± 1.2 |
|
Final hind limb caliper assessment (average both limbs-mm) |
319 ± 27 |
341 ± 23 |
|
PON1 activity [Post] (nmoles/minute/ml) |
164 ± 45* |
109 ± 28 |
|
HDL Cholesterol (mg/dL) [Pre] |
86 ± 18 |
84 ± 22 |
|
HDL Cholesterol (mg/dL) [Post] |
91 ± 21 |
91 ± 19 |
|
Total Cholesterol (mg/dL) [Pre] |
133 ± 29 |
124 ± 24 |
|
Total Cholesterol (mg/dL) [Post] |
116 ± 28 |
119 ± 22 |
|
Lactonase Activity [Pre] |
24 ± 2* |
14 ± 4 |
|
Lactonase Activity[ Post] |
23 ± 2* |
14 ± 3 |
|
Arylesterase Activity[Pre] |
134 ± 9* |
91± 26 |
|
Arylesterase Activity [Post] |
145 ± 12* |
82 ± 12 |
|
STIA Model |
||
|
PON1 activity [Pre] (nmoles/minute/ml) |
241 ± 42 * |
64 ± 18 |
|
Age (months) |
3.6 ± 0.5 |
3.9 ± 0.9 |
|
Sex (% female) |
50 |
50 |
|
Final total joint score |
7.4 ± 2.0* |
9.9 ± 1.9 |
|
Final hind limb caliper assessment (average both limbs-mm) |
375 ± 34 |
398 ± 19 |
|
PON1 activity [Post] (nmoles/minute/ml) |
186 ± 46* |
58 ± 17 |
|
Lactonase Activity [Pre] |
18 ± 2* |
9 ± 2 |
|
Lactonase Activity [Post] |
23 ± 3* |
13 ± 2 |
|
Arylesterase Activity[Pre] |
142 ± 14* |
71± 10 |
|
Arylesterase Activity[Post] |
144 ± 13* |
74± 12 |
|
HDL Cholesterol (mg/dL) [Pre] |
48 ± 11 |
62 ± 25 |
|
HDL Cholesterol (mg/dL) [Post] |
68 ± 19# |
57 ± 19 |
|
Total Cholesterol (mg/dL) [Pre] |
91 ± 19 |
101 ± 22 |
|
Total Cholesterol (mg/dL) [Post] |
111 ± 27 |
88 ± 18# |
|
Unesterified Cholesterol (mg/dL) [Pre] |
8 ± 2 |
10 ± 3 |
|
Unesterified Cholesterol (mg/dL) [Post] |
8 ± 2 |
6 ± 2# |
|
Triglycerides (mg/dL) [Pre] |
25 ± 7 |
12 ± 1 |
|
Triglycerides (mg/dL) [Post] |
19 ± 5 |
23 ± 9# |
|
Free Fatty Acids (mg/dL) [Pre] |
51 ± 7 |
71 ± 33 |
|
Free Fatty Acids (mg/dL) [Post] |
59 ± 12 |
58 ± 12 |
PONTg= mice homozygous for the PON1 human transgene. WT= wild type littermate control mice. CAIA-=collagen antibody induced arthritis. STIA= serum transfer induced arthritis. Pre=prior to arthritis induction. Post= after arthritis induction.
*p<0.05 compared to WT. # p<0.05 compared to “Pre” value of same group and test.
To cite this abstract in AMA style:
Charles-Schoeman C, Shahbazian A, Wang J, Grijalva V, Reddy ST. Decreased Inflammatory Arthritis in Human Serum Paraoxonase 1 Transgenic Mice [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/decreased-inflammatory-arthritis-in-human-serum-paraoxonase-1-transgenic-mice/. Accessed .« Back to 2017 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/decreased-inflammatory-arthritis-in-human-serum-paraoxonase-1-transgenic-mice/