Negative Regulation of Osteoclastogenesis by Inflammatory signals Rheumatoid arthritis (RA) is a chronic inflammatory disease in which immune cells and synovial fibroblasts produce pro-inflammatory cytokines, in particular TNF and IL-1, and drive an inflammatory state leading to destruction of affected joints. One important consequence of inflammation is the generation of osteoclasts, myeloid lineage cells that effectively resorb bone and thus are directly responsible for bone erosion and morbidity in RA. This application will focus on mechanisms of inhibition of the generation of osteoclasts. TLRs (Toll-like Receptors) are potent activators of inflammation and have been implicated in driving inflammatory bone resorption. However, at the same time that they activate inflammation, TLRs also induce potent homeostatic mechanisms to limit the intensity of inflammation and thus limit associated tissue damage. Disease progression is evidence of relatively ineffective feedback inhibition that is unable to restrain inflammation and bone resorption. Thus, we have initiated studies to understand the effective homeostatic regulation that occurs during physiological resolution of inflammation and quiescent phases of disease. Our overall hypothesis is that augmentation of physiological homeostatic mechanisms represents an effective approach to limiting bone resorption associated with inflammation and thus can form the basis for novel therapeutic approaches. We have found that TLR stimulation strongly suppresses osteoclastogenesis by inhibiting RANK, a key receptor required for osteoclastogenesis. The mechanism of TLR-mediated inhibition involves induction of a M-CSF receptor (c-Fms) shedding and proteolytic processing by activated TNF-alpha converting enzyme (TACE, also known as ADAM-17), potentially leading to cellular unresponsiveness to M-CSF. Cleaved c-Fms subsequently undergoes a series of proteolytic reactions that results in generation of the 50-kDa intracellular domain cleavage fragments (referred to as MICD). Interestingly, our results reveal that MICD is able to translocate into the nucleus, and expression of MICD enhances osteoclastogenesis. MICD generation is also diminished by inflammatory signals. We will use human systems that are directly relevant for RA pathogenesis as well as mouse system to test the in vivo role of MICD and TACE in inflammatory diseases. The long-term goals of this project are to: 1) understand molecular mechanisms by which c-Fms shedding and processing into MICD regulate osteoclastogenesis and the association of TACE with this process, and 2) identify the role of MICD in M-CSF signaling and differentiation of osteoclasts and macrophages. We anticipate that our studies will yield insights into homeostatic regulation that can not only be exploited for therapeutic interventions to suppress bone resorption associated with joint destruction but will also broaden understanding of the actions of M-CSF in the field of osteoimmunology.

Public Health Relevance

The erosion of bone is a key factor in the development and exacerbation of chronic inflammatory diseases, such as rheumatoid arthritis. Osteoclasts are the specific cells that cause bone erosion, and this application explores new mechanisms whereby osteoclasts can be inhibited. By deterring the development and activation of osteoclasts in inflammatory settings, we can hinder bone erosion and therefore prevent disease development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Transition Award (R00)
Project #
5R00AR061430-04
Application #
8838046
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mao, Su-Yau
Project Start
2014-04-15
Project End
2017-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
4
Fiscal Year
2015
Total Cost
$249,000
Indirect Cost
$107,523
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
Bae, Seyeon; Lee, Min Joon; Mun, Se Hwan et al. (2017) MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERR?. J Clin Invest 127:2555-2568
Park-Min, Kyung Hyun (2017) Epigenetic regulation of bone cells. Connect Tissue Res 58:76-89
Murata, Koichi; Fang, Celestia; Terao, Chikashi et al. (2017) Hypoxia-Sensitive COMMD1 Integrates Signaling and Cellular Metabolism in Human Macrophages and Suppresses Osteoclastogenesis. Immunity 47:66-79.e5
Lee, Min Joon; Lim, Elisha; Mun, Sehwan et al. (2016) Intravenous Immunoglobulin (IVIG) Attenuates TNF-Induced Pathologic Bone Resorption and Suppresses Osteoclastogenesis by Inducing A20 Expression. J Cell Physiol 231:449-458
Huynh, Linda; Kusnadi, Anthony; Park, Sung Ho et al. (2016) Opposing regulation of the late phase TNF response by mTORC1-IL-10 signaling and hypoxia in human macrophages. Sci Rep 6:31959
Fang, Celestia; Qiao, Yu; Mun, Se Hwan et al. (2016) Cutting Edge: EZH2 Promotes Osteoclastogenesis by Epigenetic Silencing of the Negative Regulator IRF8. J Immunol 196:4452-4456
Zheng, Hou-Feng; Forgetta, Vincenzo; Hsu, Yi-Hsiang et al. (2015) Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature 526:112-7
Decker, Corinne E; Yang, Zhengfeng; Rimer, Ryan et al. (2015) Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass. Proc Natl Acad Sci U S A 112:15654-9
Park-Min, Kyung-Hyun; Lim, Elisha; Lee, Min Joon et al. (2014) Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation. Nat Commun 5:5418
Issuree, Priya Darshinee A; Maretzky, Thorsten; McIlwain, David R et al. (2013) iRHOM2 is a critical pathogenic mediator of inflammatory arthritis. J Clin Invest 123:928-32