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Abstract Number: 1993

Inhibition of Choline Kinase Alpha Improves Synovitis and Cartilage Damage in Animal Models of Osteoarthritis

Roxana Coras1, Leening P Liu 2, Serena Z Shi 2, Anyan Cheng 3, Alexandra Stubelius 4, Elsa Sanchez-Lopez 5, Robert Sah 6, Ru Liu-Bryan 7 and Monica Guma 8, 1Department of Medicine, University of California San Diego, La Jolla, San Diego, CA, 2Department of Bioengineering, University of California San Diego, La Jolla, San Diego, 3Department of Medicine, University of California San Diego, La Jolla, San Diego, 4Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, San Diego, 5Department of Pharmacology, University of California San Diego, La Jolla, San Diego, 6Department of Bioengineering and Medicine, University of California San Diego, La Jolla, San Diego, 7San Diego VA/UCSD, La Jolla, CA, 8Department of Medicine, School of Medicine. University of California San Diego, La Jolla, United States

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: cartilage, choline and osteophyte, Osteoarthritis, Synovitis

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Session Information

Date: Tuesday, November 12, 2019

Title: Osteoarthritis & Joint Biology – Basic Science Poster

Session Type: Poster Session (Tuesday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Osteoarthritis (OA) is a disease of the whole joint, affecting cartilage, ligaments, menisci, bone and synovial tissue. We previously found that choline kinase alpha (ChoK) expression was upregulated in human OA synovial and cartilage tissues, and inhibition of ChoK decreased production of proinflammatory cytokines by OA synovial fibroblasts and inhibited chondrocyte catabolic responses to IL-1b in vitro. In this study, we evaluated the effects of ChoK inhibition on OA development in vivo in two animal models of OA.

Methods: Collagenase-induced osteoarthritis (CIOA) was done in 12-week old male C57BL/6 mice (intraarticular injection of 1 U of collagenase in left knee and PBS in the contralateral knee). MN58b (a ChoK inhibitor) was administered daily via intraperitoneal injection (i.p) at a dose of 2.5mg/kg. The control group received PBS i.p. Mice were sacrificed at 2 weeks. The destabilization of the medial meniscus (DMM) surgery-induced OA was performed in 12 weeks old male C57BL/6 mice on the right knee with sham surgery performed on the contralateral knee (control).  PBS or MN58b (2.5mg/kg) i.p. was administered daily for 2 weeks and then every other day until 12 weeks when mice were sacrificed. Joints were graded for synovitis (1 none to 5 severe). Micro-computed tomography (μCT) at (9 μm)3 voxel size was used to evaluate associated bone damage in the DMM model. The medial and lateral femoral condyle (MFC, LFC) and medial and lateral tibial plateau (MTP, LTP) of the arthritic and contralateral knees were registered and visualized in tri-plane orthogonal views, centered in each region, and also in periodic 2-D planes (150 per knee). Joint sections were analyzed by histology with H&E and Saf-O/FG and scored for cartilage damage and osteophyte size and maturation, as well as by immunohistochemistry, probing for ChoK, CD86 and iNOS.

Results: In CIOA, synovitis was reduced from 2.0±1.5 (range 1–5, N=13) in control mice to 0.5±1.0 (range 0–3, N=11, p=0.03) in MN58b-treated mice. Compared to the control group, the MN58b-treated CIOA joints had a lower number of infiltrating cells in the synovial membrane that were positive for ChoK, iNOS and CD86. In the DMM model, cartilage damage in the control group (4.0±2.0, range 2–6, N=9) was reduced by MN58b treatment (1.8±1.3, range 0–4, N=10, p=0.018). Furthermore, medial osteophytes in the control group (1.04±0.59, range 0–1.9) tended to be reduced in size by MN58b (0.72±0.6, range 0–1.7, p=0.1), although no difference was observed in the degree of maturation. μCT indicated that MN58b treatment reduced medial osteophyte size (by 28%, p=0.04) and medial subchondral plate thickness (by 12%, p< 0.01).

Conclusion: Our results show that ChoK inhibition reduces the degree of synovitis in CIOA animal model of OA, and cartilage damage and osteophyte size in the DMM model of OA. These findings suggest that ChoK may mediate multiple pathways of joint damage in the pathogenesis of OA and be a potential therapeutic target.


Disclosure: R. Coras, None; L. Liu, None; S. Shi, None; A. Cheng, None; A. Stubelius, None; E. Sanchez-Lopez, None; R. Sah, None; R. Liu-Bryan, None; M. Guma, None.

To cite this abstract in AMA style:

Coras R, Liu L, Shi S, Cheng A, Stubelius A, Sanchez-Lopez E, Sah R, Liu-Bryan R, Guma M. Inhibition of Choline Kinase Alpha Improves Synovitis and Cartilage Damage in Animal Models of Osteoarthritis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/inhibition-of-choline-kinase-alpha-improves-synovitis-and-cartilage-damage-in-animal-models-of-osteoarthritis/. Accessed .
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