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Bidirectional Notch Signaling and Osteocyte-Derived Factors in The Published OnlineFirst February 1, 2016; DOI: 10.1158/0008-5472.CAN-15-1703 Cancer Molecular and Cellular Pathobiology Research Bidirectional Notch Signaling and Osteocyte- Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma Jesus Delgado-Calle1,2, Judith Anderson3, Meloney D. Cregor1, Masahiro Hiasa3, John M. Chirgwin2,4, Nadia Carlesso5, Toshiyuki Yoneda3, Khalid S. Mohammad1,4, Lilian I. Plotkin1,2, G. David Roodman2,3, and Teresita Bellido1,2,4 Abstract In multiple myeloma, an overabundance of monoclonal sion, the osteocytic Rankl/Opg (TNFRSF11B) ratio, and the plasma cells in the bone marrow induces localized osteolytic ability of osteocytes to attract osteoclast precursors to induce lesions that rarely heal due to increased bone resorption and local bone resorption. Furthermore, osteocytes in contact suppressed bone formation. Matrix-embedded osteocytes with multiple myeloma cells expressed high levels of Sost/ comprise more than 95% of bone cells and are major reg- sclerostin, leading to a reduction in Wnt signaling and ulators of osteoclast and osteoblast activity, but their con- subsequent inhibition of osteoblast differentiation. Impor- tribution to multiple myeloma growth and bone disease is tantly, direct contact between osteocytes and multiple mye- unknown. Here, we report that osteocytes in a mouse model loma cells reciprocally activated Notch signaling and of human MM physically interact with multiple myeloma increased Notch receptor expression, particularly Notch3 and cells in vivo, undergo caspase-3–dependent apoptosis, and 4, stimulating multiple myeloma cell growth. These studies express higher RANKL (TNFSF11) and sclerostin levels reveal a previously unknown role for bidirectional Notch than osteocytes in control mice. Mechanistic studies reveal- signaling that enhances MM growth and bone disease, sug- ed that osteocyte apoptosis was initiated by multiple mye- gesting that targeting osteocyte-multiple myeloma cell inter- loma cell-mediated activation of Notch signaling and was actions through specific Notch receptor blockade may repre- further amplified by multiple myeloma cell-secreted TNF. sent a promising treatment strategy in multiple myeloma. The induction of apoptosis increased osteocytic Rankl expres- Cancer Res; 76(5); 1–12. Ó2016 AACR. Introduction increased bone resorption and concomitant long-term suppres- sion of bone formation. The bone/BM microenvironment is a Multiple myeloma is characterized by expansion of monoclo- major contributor to tumor growth and bone destruction in nal plasma cells in the bone marrow (BM) that induce marked multiple myeloma (3). The bone remodeling compartment is bone destruction in the majority of patients (1). Multiple mye- disrupted in multiple myeloma, allowing exchange of soluble loma patients present with severe bone pain caused by osteolytic factors and direct cell-to-cell contact between multiple myelo- lesions that rarely heal (2). The osteolytic lesions result from ma cells and bone cells (4). Previous studies demonstrated that multiple cytokines are secreted or induced by the interaction of 1Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana. 2Roudebush Veterans Administra- multiple myeloma cells with the different cell types in the bone tion Medical Center, Indianapolis, Indiana. 3Division of Hematology/ microenvironment to increase bone destruction, including the Oncology, Department of Medicine, Indiana University School of Med- receptor of activator nuclear factor-kappa B ligand (RANKL), 4 icine, Indianapolis, Indiana. Division of Endocrinology, Department of the chemokine (C-C motif) ligand 3 (MIP1a), and IL3. Further, Medicine, Indiana University School of Medicine, Indianapolis, Indiana. 5Department of Pediatrics Indiana, University School of Medicine, multiple myeloma–derived IL7, dickkopf WNT signaling path- Indianapolis, Indiana. way inhibitor 1 (DKK1), and IL3, as well as direct contact by Note: Supplementary data for this article are available at Cancer Research multiple myeloma cells with osteoblasts inhibit osteoblast Online (http://cancerres.aacrjournals.org/). differentiation (1, 5). Corresponding Authors: Teresita Bellido, Indiana University School of Medicine, Although osteoclasts and osteoblasts remodel bone by 635 Barnhill Drive Medical Science Building, Room 5045A, Indianapolis, IN resorbing or forming bone respectively, osteocytes, which con- 46202. Phone: 317-274-7410; Fax: 317-278-2040; E-mail: [email protected]; stitute >95% of all bone cells, are the central regulators of these or G. David Roodman, Indiana University School of Medicine, 980 W. Walnut processes (6, 7). Osteocytes, although buried within bone Street, Suite C312, Indianapolis, IN 46202. Phone: 317-278-6255; Fax: 317-274- mineral, extensively communicate with each other and with 0396; E-mail: [email protected] cells on the bone surface and in the marrow via cytoplasmic doi: 10.1158/0008-5472.CAN-15-1703 projections that run along canaliculi and form the osteocyte Ó2016 American Association for Cancer Research. network. This network allows cell-to-cell communication and www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst February 1, 2016; DOI: 10.1158/0008-5472.CAN-15-1703 Delgado-Calle et al. distributes osteocyte-secreted molecules that regulate osteo- Ex vivo bone organ cultures blast and osteoclast function. Osteocytes are the primary pro- These assays were performed as previously described (21). ducers of sclerostin, the product of the SOST gene, a potent Detailed description of the assay can be found in Supplementary inhibitor of bone formation, and are a major source of RANKL, Methods. the central osteoclastogenic factor (8, 9). Lack of sclerostin increases osteoblast number and activity, and deletion of Cell viability and apoptosis osteocytic RANKL inhibits osteoclast formation and bone Multiple myeloma cells were separated from adherent osteo- resorption, demonstrating that osteocytes are key regulators cyte-like cells using EDTA. Cell death was quantified by trypan – of osteoblast and osteoclast activity (10 12). Moreover, apo- blue uptake and apoptosis by chromatin condensation and ptotic osteocytes, which accumulate with skeletal disuse, glu- nuclear fragmentation of cells transfected with nuclear green fi cocorticoid excess, or estrogen de ciency, increase local bone fluorescent protein (nGFP; refs. 22, 23). At least 100 cells in five resorption by attracting osteoclast precursors to particular different fields selected by systematic random sampling were areas of bone (6, 13). Although knowledge of the role of examined for each experimental condition. Representative photo- osteocytes and the osteocytic network in bone homeostasis micrographs were taken with an EVOS FLCell Imaging System and common skeletal diseases has greatly increased, the con- (Life Technologies). tribution of osteocytes to the development and progression of cancer involving bone is just beginning to be defined. In the current study, we determined if reciprocal communica- Cell proliferation analysis tion between multiple myeloma cells and osteocytes occurs and Viable cells were enumerated by trypan blue exclusion. Fluo- explored the mechanisms involved and the consequences of these rescence emitted by 5TGM1-GFP cells was measured in a Spec- interactions for the progression of multiple myeloma bone traMaxi3 microplate reader (Molecular Devices), set at 485 nm/ disease. 520 nm. 5TGM1-GFP cell numbers linearly correlated with rela- tive fluorescent units (RFU; Supplementary Fig. S1A). Materials and Methods Transfections Reagents MLO-A5 cells were transiently transfected using Lipofectamine- Reagents used in this study can be found in Supplementary Plus (Invitrogen; refs. 23, 24). Methods. Gene expression analysis Cells and culture conditions mRNA expression was quantified as previously described (25). L. Bonewald (University of Missouri–Kansas City, Kansas Murine soluble RANKL, OPG, or human TNFa were quantified by City, MO) provided the murine MLO-A5 in 1997 and MLO-Y4 ELISA (R&D Systems) of culture supernatants. in 2001 osteocyte-like cells (14, 15). JJN3, 5TGM1, and MM1.S multiple myeloma cell lines were provided by N. Giuliani (University of Parma, Parma, Italy) in 2006, B. Oyajobi (Uni- Western blot analysis versity of Texas at San Antonio, San Antonio, TX) in 2007, and The assays were performed as described previously (25). S. Rosen (Northwestern University, Evanston, IL) in 2003 (16– Detailed descriptions of antibodies can be found in Supplemen- 18). R. Jilka (University of Arkansas for Medical Sciences, Little tary Methods. Rock, AR) provided the OB-6 osteoblast–like cells in 1997 (19). Nonadherent osteoclast precursors were collected as described þ Osteoclast precursor migration before (20). After informed consent, CD138 cells from multiple Forty-eight–hour CM from JJN3, MLO-A5, or from JJN3 and myeloma patients were prepared as previously detailed (16). MLO-A5 cocultured in direct contact was placed in the bottom of Studies were approved by the Indiana University School of 8-mm pore chambers to attract murine nonadherent BM cells (26). Medicine Institutional Review Board. Cell lines were authenti- Detailed description of the assay can be found in Supplementary fi cated by morphology, gene expression pro le, and tumorigenic Methods. capacity (multiple myeloma
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