Date of Award

Summer 8-15-2015

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Pathological bone loss in human disease such as arthritis is largely due to excessive osteoclast recruitment as a consequence of localized inflammation. Innate immune cells, namely neutrophils and macrophages, infiltrate the joint space and release pro-inflammatory cytokines as well as proteases to drive local tissue damage and inflammation. Importantly, IL-1 and TNF-a in particular act on the synovial fibroblasts as well as directly on osteoclast precursors to potently augment osteoclast differentiation and thus bone resorption. Current therapeutics to treat pathological bone loss are widely unsuccessful at targeting both the resorptive and inflammatory components of disease. We have previously demonstrated that phospholipase C gamma-2 (PLCγ2) regulates both the osteoclast and innate immune cell functions. PLCγ2-/- mice are osteopetrotic resulting from defective OC formation and are protected from inflammatory bone loss due to impaired innate immune responses. While PLCγ2 function can be specifically repressed in the osteoclast via SH2 domain targeting, this approach does not block inflammation in vivo. Thus we sought to identify specific downstream targets of PLCγ2 that could regulate both the osteoclast and innate immune responses in arthritis.

By a gene array approach, we identified the previously undescribed protein Tmem178 as a novel PLCγ2 effector whose expression is highly induced by RANKL stimulation, integrin-mediated adhesion, and TLR activation in WT but not PLCγ2-/-macrophages. Importantly, Tmem178 expression is confined to macrophages and osteoclasts and not in other bone marrow-derived cells or immune cell types such as T cells. In surprising contrast to the osteopetrotic phenotype of PLCγ2-/- mice, Tmem178-/- mice are osteopenic in basal conditions and are more susceptible to inflammatory bone loss, owing to enhanced osteoclast formation. We also find that Tmem178-null mice succumb faster to endotoxin-induced sepsis due to an increase in inflammatory cytokine production by macrophages. Mechanistically, Tmem178 localizes to the endoplasmic reticulum membrane where it interacts with the Ca2+-sensing protein Stim1. In the ER, Tmem178 acts to restrain Ca2+ release, thus controlling activation of the transcription factor NFAT which is central to both osteoclast differentiation and pro-inflammatory cytokine production. Importantly, downregulation of Tmem178 is observed in human CD14+ monocytes exposed to plasma from systemic juvenile idiopathic arthritis patients. This defective Tmem178 expression correlates with augmented osteoclastogenesis in vitro and erosive disease in vivo, suggesting that Tmem178 may also play a fundamental role in controlling arthritic disease in humans. In sum, this dissertation identifies the first known function of Tmem178 in any cell type and positions Tmem178 as an essential regulatory component in both the inflammatory and erosive arms of pathological bone loss.


English (en)

Chair and Committee

Roberta Faccio

Committee Members

Kyunghee Choi, Mary Dinauer, Marco Colonna, Deborah Novack, Steven Teitelbaum,


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