Associate Member of the Staff
Department of Cytokine Biology
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The secreted phosphoprotein osteopontin (OPN) has multiple effects in the body’s response to injury and inflammation. This variably phosphorylated and glycosylated protein is expressed in numerous cell types, and its pro-inflammatory properties are mediated at least in part through its ability to regulate T-cell subsets and to enhance dendritic cell function. Oral infections including periodontitis and endodontic (involving the tooth root) infections are some of the most common infections in the world, affecting millions in North America alone. We are studying the effects of osteopontin in the response to these oral infections. In collaboration with Dr. Hajime Sasaki we have recently shown that mice that lack osteopontin have an exaggerated inflammatory response to endodontic infection, such that the bone loss associated with this disease is greatly increased in mice lacking osteopontin expression. Analysis of cytokine expression in these infections suggests that OPN may function to enhance the innate immune response to bacterial infections, a function that contrasts with its characterized role in the adaptive immune system. A current focus of the lab is to understand the mechanism of OPN function in these infections, and to evaluate the effect of OPN in similar infections such as periodontitis and colitis. Our results and those of others suggest that OPN has a protective role in these infections, and may have important therapeutic value. Since osteopontin is variably post-translationally modified, we seek to understand the role of these modifications in osteopontin function in vivo and in vitro, in order to design the most appropriate therapeutic forms of the protein.
An additional area of interest is the interaction of tumor and bone cells during the process of bone metastasis. Many tumor types, including breast cancers, spread or metastasize to the bone; indeed bone is the most common site of bone metastasis in women with metastatic breast cancer. Tumors growing in the bone cause severe and rapid bone loss; these painful and essentially incurable lesions have serious quality of life consequences and frequently result in fractures and loss of mobility. Osteoclasts are terminally differentiated cells that function to destroy bone. We are working to understand the mechanisms tumor cells use to activate osteoclasts. Osteopontin is required for maximal osteoclast function, but the defect in these cells in OPN-deficient mice is overridden in both infection-related bone loss and in tumor-associated bone loss. Thus, an additional focus in the lab is understanding the mechanisms by which these two processes result in hyperactivated, osteopontin independent osteoclasts. One potential mechanism we have identified is the osteoclast growth factor CSF-1, which is made by tumor cells as both cell-surface associated and secreted forms: both these forms of the protein may be important in the development of hyperactivated osteoclasts.
Rittling SR, Zetterberg C, Yagiz K, Skinner S, Suzuki N, Fujimura A, Sasaki H. (2010) Protective role ofosteopontin in endodontic infection. Immunology 129(1):105-114.
Maeno Y, Shinzato M, nagashima S, Rittling SR, Denhardt DT, Uede T, Taniguchi K. (2009) Effect of osteopontin on diarrhea duration and innate immunity in suckling mice infected with a murine rotavirus. Viral Immunol. 22(2):139-144.
Yagiz K, Rittling SR. (2009) Both cell-surface and secreted CSF-1 expressed by tumor cells metastatic to bone can contribute to osteoclast activation. Exp. Cell Res. 315(14):2442-2452.
Diao H, Iwabuchi K, Li L, Onoe K, Van Kaer L, Kon S, Saito Y, Morimoto J, Denhardt DT, Rittling S, Uede T. 2008. Osteopontin regulates development and function of invariant natural killer T cells. Proc. Natl. Acad. Sci. U S A 105(41):15884-15889.
Sato I, Yamamoto N, Rittling SR, Denhardt DT, Hino M, Morimoro J, Sakai F, Fujie A, Uede T. (2008) Osteopontin is dispensable for protection against high load systemic fungal infection. Int. Immunopharmacol. 8(10):1441-1448.
Ramaiah SK, Rittling S. (2008) Pathophysiological role of osteopontin in hepatic inflammation, toxicity and cancer. Toxicol. Sci. 103(1):4-13.
Kazanecki CC, Kowalski AJ, Ding T, Rittling SR, Denhardt DT. (2007) Characterization of anti-osteopontin monoclonal antibodies: Binding sensitivity to post-translational modifications. J. Cell. Biochem. 102(4):925-935.
Christensen B, Kazanecki CC, Petersen TE, Rittling SR, Denhardt DT, Sørensen ES. (2007) Cell-type specific post-translational modifications of mouse osteopontin are associated with different adhesive proper-ties. J. Biol. Chem. 282(27):19463-19472.
Yates B, Zetterberg C, Rajeev V, Reiss M, Rittling SR. (2007) Promoter-independent regulation of vimentin expression in mammary epithelial cells by val12 ras and TGFß. Exp. Cell Res. 313(17):3718-3728.
Natasha T, Kuhn M, Kelly O, Rittling SR. (2006) Override of the osteoclast defect in osteopontin-deficient mice by metastatic tumor growth in the bone. Am. J. Pathol. 168(2):551-561.
Ge R, Rajeev V, Ray P, Lattime E, Rittling S, Medicherla S, Protter A, Murphy A, Chakravarty J, Dugar S, Schreiner G, Barnard N, Reiss M. (2006) Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-beta type 1 receptor kinase in vivo. Clin. Cancer Res. 12(14 Pt. 1):4315-4330.
da Silva AP, Pollett A, Rittling SR, Denhardt DT, Sodek J, Zobar R. (2006) Exacerbated tissue destruction in DSS-induced acute colitis of OPN-null mice is associated with downregulation of TNF-alpha expression and non-programmed cell death. J. Cell Physiol. 208(3):629-639.
Kuhn M, Shah S, Natasha T, Rittling SR. (2006) A mouse model of breast cancer metastasis to the choroid of the eye. Clin. Exp. Metastasis 22(8):685-690
