Inhibition of p38 Mitogen-Activated Protein Kinase Prevents the Development of Osteolytic Bone Disease, Reduces Tumor Burden, and Increases Survival in Murine Models of Multiple Myeloma

^{1 1}Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium; ²Scios, Inc., Fremont, California; ³Academic Unit of Bone Biology, University of Sheffield School of Medicine and Biomedical Science, Sheffield, United Kingdom; and ⁴Department of Pathology, University Hospital Antwerp, Antwerp, Belgium

^* To whom correspondence should be addressed. E-mail: Karin.Vanderkerken{at}vub.ac.be.

	Abstract

The bone microenvironment plays a critical role in supporting the growth and survival of multiple myeloma as well as in the development of osteolytic bone disease. Signaling through p38 mitogen-activated protein kinase (MAPK) mediates synthesis of multiple myeloma cell growth factors, and its inhibition reduces proliferation in vitro. However, it is unclear whether targeting p38 MAPK prevents multiple myeloma growth and the development of bone disease in vivo. In this study, we determined whether SCIO-469, a selective p38 MAPK inhibitor, inhibits multiple myeloma growth and prevents bone disease in the 5T2MM and 5T33MM models. SCIO-469 decreased constitutive p38 MAPK phosphorylation of both 5T2MM and 5T33MM cells in vitro. This was associated with decreased DNA synthesis and an induction of apoptosis when the cells were cultured with bone marrow stromal cells. Treatment of C57Bl/KaLwRij mice bearing 5T33MM cells with SCIO-469 inhibited p38 MAPK phosphorylation and was associated with a significant decrease in serum paraprotein, an almost complete reduction in tumor cells in the bone marrow, a decrease in angiogenesis, and a significant increase in disease-free survival. Injection of 5T2MM murine myeloma cells into C57Bl/KaLwRij mice resulted in myeloma bone disease characterized by increased osteoclast occupation of the bone surface, reduced cancellous bone, and the development of osteolytic bone lesions. Treatment of 5T2MM-injected mice with SCIO-469 reduced this development of bone disease. Together, these data show that targeting p38 MAPK with SCIO-469 decreases myeloma burden in vivo, in addition to preventing the development of myeloma bone disease. [Cancer Res 2007;67(10):4573-7]

Key Words: Myeloma, Bone, p38 MAPK, Osteoclast