Innate immune mechanisms of osteoarthritis
Abstract/Contents
- Abstract
- The pathogenesis of osteoarthritis (OA), the most common disease of the joints, remains unclear and there are currently no treatments that can prevent or slow disease progression. Although synovitis (i.e., inflammation of the membrane that lines synovial joints) and mildly elevated levels of white blood cells in synovial fluid are well-established features of osteoarthritis, the role of inflammation in osteoarthritis, as well as the precise cellular and molecular mechanisms involved, are unknown. The studies presented in this dissertation support our overarching hypothesis that chronic, low-grade inflammation and activation of the innate immune system drive OA pathogenesis. In Chapter 2, we demonstrate a key pathogenic role for mast cells in OA. Genetic deficiency of mast cells protects against OA, and engraftment of mast cells reverses this protection. Furthermore, transcriptomic and proteomic analyses of OA synovial tissues and fluids demonstrate evidence of mast cell activation in human disease. In vitro studies support a mechanistic role for tryptase as a mediator of mast cell-driven pathology in OA: tryptase promotes cartilage catabolism, induces chondrocyte apoptosis, and stimulates proliferation and proinflammatory responses of synovial fibroblasts. In Chapter 3, we demonstrate that the complement system, acting through its membrane attack complex-mediated arm, is pathogenic in OA. Genetic deficiency of complement components C5 and C6 or pharmacologic inhibition of complement with either CR2-fH, a fusion protein that inhibits activation of C3 and C5, or a monoclonal antibody to C5 attenuates joint damage in a mouse model of OA, whereas deficiency of the MAC-inhibitor CD59a exacerbates disease. Moreover, complement expression is dysregulated in human OA, and MAC, when present on the cell surface at sublytic concentrations, induces chondrocyte expression of proinflammatory mediators and degradative enzymes relevant to OA. Finally, in Chapter 4, we demonstrate that Carboxypeptidase B (CPB) protects against OA, and it does so in part by inhibiting complement activation. Genetic deficiency of CPB exacerbates OA in mice. Moreover, we show that levels of CPB strongly correlate with levels of MAC in OA synovial fluid, and CPB inhibits MAC formation and activity in vitro. Taken together, our findings emphasize the significance of innate immune responses in OA pathogenesis and support a thorough reexamination of the prevailing dogma that osteoarthritis is a non-inflammatory, 'wear and tear' arthritis. Furthermore, our increased understanding of the inflammatory underpinnings of OA suggests multiple avenues for the development of new, disease-modifying therapies.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2016 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Lepus, Christin Marie |
|---|---|
| Associated with | Stanford University, Program in Immunology. |
| Primary advisor | Robinson, William (William Hewitt) |
| Thesis advisor | Robinson, William (William Hewitt) |
| Thesis advisor | Fathman, C. Garrison |
| Thesis advisor | Miklos, David (David B.) |
| Thesis advisor | Wyss-Coray, Anton |
| Advisor | Fathman, C. Garrison |
| Advisor | Miklos, David (David B.) |
| Advisor | Wyss-Coray, Anton |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Christin Marie Lepus. |
|---|---|
| Note | Submitted to the Program in Immunology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2016. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2016 by Christin Marie Lepus
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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