Osteogenic Factors: Novel Targets to Attenuate Excessive Bone Degradation during Autoimmune Arthritis

Date of Award

2016

Degree Type

Thesis

Degree Name

Master of Science (MS)

First Advisor

Bonnie Buxton, PhD

Second Advisor

Srujana Rayalam, BVSc, MVSc, PhD

Third Advisor

Xinyu (Eric) Wang, PhD

Fourth Advisor

Richard White PhD, F AHA

Fifth Advisor

Rangaiah Shashidharamurthy, PhD

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease associated with severe bone erosions of joints, which lead to crippling disability. It has been shown that bone resorbing cells such as osteoclasts are mainly responsible for excessive bone degradation during RA. In the past, several drugs have been developed to inhibit differentiation and maturation of osteoclasts to prevent the excessive bone degradation autoimmune arthritis. However, these drugs are potent immunosuppressives and lead to severe infections. Recent studies have shown that the translocation of nuclear factor kappa B (NF-κB) to the nucleus is the key event during which the differentiation of pre-osteoclasts to mature osteoclasts occurs. This distinctive formation is responsible for excessive bone degradation in RA. However, there are other osteogenic factors which are necessary to propagate the development of these cells such as NFATcl and cFos. Both of these factors play an important role in contributing to the maturation of osteoclast development. Therefore, we hypothesize that inhibiting the translocation of NF-κB as well as other key inflammatory factors may offer an innovative and alternative strategy to treat/prevent severe bone degeneration. The goal of this project is to investigate whether the inhibition of NF-κB, NFATcl, or cFos translocation is a useful strategy to blunt the osteoclast differentiation during the development of arthritis. To achieve this objective, we will use recently discovered anti-osteoclastogenic agents such as Lipocalin-2, an innate immune protein and also the small molecular weight antioxidant flavonoid, Caffeic Acid Phenethyl Ester (CAPE), and its newly discovered derivative (F-CAPE). Our studies suggest that F-CAPE is a novel Holland iv pharmacological inhibitor of osteoclast maturation from monocytic precursor cells. Mechanistically F-CAPE inhibits cFos upregulation during late stage of osteoclast maturation and thereby inhibits complex formation NF-κB, cFos and NFATcl, a key event during osteoclast formation. These studies also suggest that the F-CAPE is a more potent molecule than parental CAPE. In addition, we have demonstrated that lipocalin2 uptake through its receptor 24p3R is essential for osteoclast formation. Taken together, these studies suggest that targeting the key factors responsible for osteoclast formation is a novel approach to blunt/attenuate excessive bone loss during autoinflammatory arthritis such as RA.

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