Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Cell Biology

Language

English (en)

Date of Award

1-1-2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Steven Teitelbaum

Abstract

Osteoclasts are essential for skeletal homeostasis: Teitelbaum, 2000). These macrophage-lineage cells function by generating a polarized microenvironment between themselves and bone wherein skeletal matrix is degraded. This resorptive compartment is isolated from the general extracellular space by an actin ring which encompasses the ruffled border, a convoluted plasma membrane structure formed by its fusion with lysosome-related vesicles containing an electrogenic H+ATPase, a chloride channel, LAMP-1, and cathepsin K. In consequence, resorption of bone reflects secretion of HCl to mobilize mineral, and cathepsin K to degrade the collagen-rich organic matrix, into the resorptive space: Stenbeck, 2002; Zhao et al., 2008). We determined that the two ubiquitin-like conjugation systems required for macroautophagy are necessary for generation of the osteoclast ruffled border. These autophagy proteins regulate the cell's capacity to efficiently secrete lysosomal proteins into the resorptive microenvironment both in vitro and in vivo and thus its ability to degrade bone. These findings provide a novel role for autophagy proteins and a possible mechanism to explain human genome wide association data suggesting a link between the autophagy pathway and predisposition to osteoporosis: Zhang et al.). Further studies in this thesis implicate IL-17 signaling in osteoporosis. Although not traditionally thought of as an inflammatory disease, estrogen deficiency osteoporosis is partially mediated by T cells, at least in mice: Weitzmann and Pacifici, 2007). Th17 cells, which secrete IL-17, mediate a number of inflammatory and autoimmune conditions, including arthritis-mediated bone destruction. We find IL-17 critical in the pathogenesis of bone loss due to estrogen deficiency. IL-17 receptor deficient mice are protected from bone loss after ovariectomy, as are mice treated with a neutralizing IL-17 antibody. Mice treated with a small molecule inhibitor of IL-17 production are similarly protected. The effect of IL-17 on osteoclasts is indirect, via osteoblastic upregulation of RANKL. The SEFIR domain of IL-17R is critical for osteoblast-mediated osteoclast formation and RANKL production. The adaptor protein Act1, specifically its SEFIR domain, is required for osteoblast-mediated osteoclast formation in response to IL-17, and Act1-/- mice are also protected from bone loss induced by estrogen deficiency.

Comments

Permanent URL: http://dx.doi.org/10.7936/K73N21D8

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