Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo

Abstract

There is increasing evidence to suggest that the Wnt signaling pathway plays a critical role in the pathogenesis of myeloma bone disease. In the present study, we determined whether increasing Wnt signaling within the bone marrow microenvironment in myeloma counteracts development of osteolytic bone disease. C57BL/KaLwRij mice were inoculated intravenously with murine 5TGM1 myeloma cells, resulting in tumor growth in bone and development of myeloma bone disease. Lithium chloride (LiCl) treatment activated Wnt signaling in osteoblasts, inhibited myeloma bone disease, and decreased tumor burden in bone, but increased tumor growth when 5TGM1 cells were inoculated subcutaneously. Abrogation of beta-catenin activity and disruption of Wnt signaling in 5TGM1 cells by stable overexpression of a dominant-negative TCF4 prevented the LiCl-induced increase in subcutaneous growth but had no effect on LiCl-induced reduction in tumor burden within bone or on osteolysis in myeloma-bearing mice. Together, these data highlight the importance of the local microenvironment in the effect of Wnt signaling on the development of myeloma bone disease and demonstrate that, despite a direct effect to increase tumor growth at extraosseous sites, increasing Wnt signaling in the bone marrow microenvironment can prevent the development of myeloma bone disease and inhibit myeloma growth within bone in vivo.

Myeloma plasma cells alter the bone marrow microenvironment by stimulating the proliferation of mesenchymal stromal cells

“…49,50 BIO has been shown to increase bone volume in wild-type mice and may function to decrease MM tumor burden specifically in the context of the bone microenvironment. 51,52 Similarly, purmorphamine, a Hedgehog (Hh) pathway agonist that functions through the receptor Smoothened to enhance osteogenesis of murine-derived MSC 53,54 has been shown to have a pro-osteogenic effect on human-derived MSC. 55,56 Another small molecule, decalpenic acid (CR37010), was also identified as having the capacity to induce early osteogenic markers in murine pluripotent MSC; 57,58 however, this has not yet been demonstrated in a human setting.…”

Bone Anabolic Agents for the Treatment of Multiple Myeloma

“…Coculture data showed a diminished tumor cell proliferation in the presence of OBs compared to OCs or BMSCs [10]. Increased OB differentiation, via up-regulation of the osteogenic signaling β-catenin, results in tumor growth inhibition in murine models of myeloma bone disease [15]. Although the mechanism of inhibition remains unclear, small leucinerich proteoglycans may be involved.…”

Preclinical animal models of multiple myeloma

“…Subcutaneous injection of human myeloma cells may require matrigel for successful tumor infiltration in xenograft models, 5 whereas murine myeloma cells grow well in C57BL/KaLwRij mice without a requirement for matrigel. 6 6. Inject 100 ml of PBS for non-tumor control mice.…”