Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma.
Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-α, transforming growth factor-β (TGF-β) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF-β signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell-bone marrow interaction.
1] Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan [2] Department of Biomaterials and Bioengineering, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan [3] Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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M
Hiasa
Department of Histology and Oral Histology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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J
Teramachi
Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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A
Oda
Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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Amachi
Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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Harada
Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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Nakamura
Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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H
Miki
Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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S
Fujii
Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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Kagawa
Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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Watanabe
Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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Endo
Department of Hematology and Oncology, RIRBM, Hiroshima University, Hiroshima, Japan.
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Y
Kuroda
Department of Medicine, Hematology Oncology, Indiana University, Indianapolis, IN, USA.
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Yoneda
Department of Medicinal Biotechnology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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D
Tsuji
Department of Molecular Medicinal Chemistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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M
Nakao
Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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0000000227071613
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Tanaka
Department of Biomaterials and Bioengineering, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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K
Hamada
Department of Molecular Medicinal Chemistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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Sano
Department of Medicinal Biotechnology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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K
Itoh
Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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T
Matsumoto
Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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Abe
D001483:Base Sequence; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D017931:DNA Primers; D018450:Disease Progression; D006801:Humans; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D010006:Osteoblasts / Q000166:cytology; D010024:Osteoporosis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
D055396:Bone Morphogenetic Protein 2; D017931:DNA Primers; C490587:PIM2 protein, human; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases