""""""""Cherubism"""""""" is a human autosomal dominant disorder characterized by excessive bone resorption and the accumulation of inflammatory fibrous tissue in the jaws. We identified the gene responsible for this human disease, a signaling adaptor protein called """"""""SH3 domain binding protein 2 (SH3BP2)"""""""", and pinpointed the mutations responsible for this condition. To further investigate the pathogenesis of Cherubism, we have generated a knock-in mouse model carrying this mutation (P416R in mice). Similar to the human disease, the cherubism mice exhibit systemic macrophage-driven inflammation with increased tumor necrosis factor-alpha (TNF-1) production as well as enhanced osteoclast differentiation, resulting in severe systemic inflammatory bone loss. Therefore these mice are useful, not only as a model of cherubism, but also potentially as a model for other inflammatory bone diseases. The overall hypothesis for the proposed studies is that the misexpression and disregulation of TNF-1 in Cherubism-associated inflammatory bone disease is mediated through SH3BP2 signaling in myeloid lineage cells. We propose SH3BP2 mutations result in abnormal signaling in macrophages and osteoclast precursors in response to macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-KB (NF-KB) ligand (RANKL), respectively. We also propose that the hyperactive macrophages are responsible for elevated TNF-1 which can feed back to further activate the osteoclasts, already made hyperactive through mutant SH3BP2. Our preliminary data suggest that ERK and MyD88 are involved in TNF- 1 production by hyperactive macrophages, while Syk and NFATc1 are involved in osteoclast hyperactivation. To test these hypotheses, the following specific aims are proposed: 1) Determine the mechanisms by which SH3BP2 regulates TNF-1 production in macrophages, 2) Determine the role of SH3BP2 in NFATc1-mediated osteoclast differentiation, and 3) Determine the role of the MyD88-mediated signaling pathway in the pathogenesis of inflammation in cherubism. The cherubism mouse model will be crossed with other mouse models such as the SHP-1 and MyD88 null mice in conjunction with relevant in vitro assays to test these hypotheses. Detailed analyses of the SH3BP2- and MyD88-mediated signaling pathway, the production of TNF-1 and their roles in inflammation and osteoclast activation will greatly contribute to better understanding of inflammatory bone disease in cherubism. Identifying the molecular components of these pathways and how they function will also aid in developing new targets for therapeutic intervention for other inflammatory diseases, such as rheumatoid arthritis and periodontal disease.

Public Health Relevance

The goal of this project is to identify the novel molecular pathways involved in the inflammatory bone disease associated with Cherubism. Successful identification of these pathways will facilitate the design of more effective drugs for the treatment of patients suffering from Cherubism as well as other inflammatory diseases such as rheumatoid arthritis and periodontal disease.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Wan, Jason
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University of Missouri Kansas City
Schools of Dentistry
Kansas City
United States
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Kittaka, Mizuho; Mayahara, Kotoe; Mukai, Tomoyuki et al. (2018) Cherubism Mice Also Deficient in c-Fos Exhibit Inflammatory Bone Destruction Executed by Macrophages That Express MMP14 Despite the Absence of TRAP+ Osteoclasts. J Bone Miner Res 33:167-181
Yoshitaka, Teruhito; Kittaka, Mizuho; Ishida, Shu et al. (2015) Bone marrow transplantation improves autoinflammation and inflammatory bone loss in SH3BP2 knock-in cherubism mice. Bone 71:201-9
Mukai, Tomoyuki; Gallant, Richard; Ishida, Shu et al. (2015) Loss of SH3 domain-binding protein 2 function suppresses bone destruction in tumor necrosis factor-driven and collagen-induced arthritis in mice. Arthritis Rheumatol 67:656-67
Mukai, Tomoyuki; Ishida, Shu; Ishikawa, Remi et al. (2014) SH3BP2 cherubism mutation potentiates TNF-?-induced osteoclastogenesis via NFATc1 and TNF-?-mediated inflammatory bone loss. J Bone Miner Res 29:2618-35
Mukai, Tomoyuki; Gallant, Richard; Ishida, Shu et al. (2014) SH3BP2 gain-of-function mutation exacerbates inflammation and bone loss in a murine collagen-induced arthritis model. PLoS One 9:e105518
Yoshitaka, Teruhito; Mukai, Tomoyuki; Kittaka, Mizuho et al. (2014) Enhanced TLR-MYD88 signaling stimulates autoinflammation in SH3BP2 cherubism mice and defines the etiology of cherubism. Cell Rep 8:1752-1766
Yoshitaka, Teruhito; Ishida, Shu; Mukai, Tomoyuki et al. (2014) Etanercept administration to neonatal SH3BP2 knock-in cherubism mice prevents TNF-?-induced inflammation and bone loss. J Bone Miner Res 29:1170-82
Levaot, Noam; Voytyuk, Oleksandr; Dimitriou, Ioannis et al. (2011) Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism. Cell 147:1324-39
Mukherjee, Padma M; Wang, Chiachien J; Chen, I-Ping et al. (2010) Cherubism gene Sh3bp2 is important for optimal bone formation, osteoblast differentiation, and function. Am J Orthod Dentofacial Orthop 138:140.e1-140.e11; discussion 140-
Wang, Chiachien J; Chen, I-Ping; Koczon-Jaremko, Boguslawa et al. (2010) Pro416Arg cherubism mutation in Sh3bp2 knock-in mice affects osteoblasts and alters bone mineral and matrix properties. Bone 46:1306-15