1 research outputs found
Differential pain-related behaviors and bone disease in immunocompetent mouse models of myeloma
Bone pain is a serious and debilitating symptom of multiple myeloma (MM) that impairs the quality of life of patients. The underlying mechanisms of the pain are unknown and understudied, and there is a need for immunocompetent preclinical models of myelomaâinduced bone pain. The aim of this study was to provide the first inâdepth behavioral characterization of an immunocompetent mouse model of MM presenting the clinical disease features: osteolytic bone disease and bone pain. We hypothesized that a widely used syngeneic model of MM, established by systemic inoculation of green fluorescent proteinâtagged myeloma cells (5TGM1âGFP) in immunocompetent C57Bl/KaLwRijHsd (BKAL) mice, would present painârelated behaviors. Disease phenotype was confirmed by splenomegaly, high serum paraprotein, and tumor infiltration in the bone marrow of the hind limbs; however, myelomaâbearing mice did not present painârelated behaviors or substantial bone disease. Thus, we investigated an alternative model in which 5TGM1âGFP cells were directly inoculated into the intrafemoral medullary cavity. This localized myeloma model presented the hallmarks of the disease, including high serum paraprotein, tumor growth, and osteolytic bone lesions. Compared with control mice, myelomaâbearing mice presented myelomaâinduced painârelated behaviors, a phenotype that was reversed by systemic morphine treatment. Microâcomputed tomography analyses of the myelomaâinoculated femurs showed bone disease in cortical and trabecular bone. Repeated systemic bisphosphonate treatment induced an amelioration of the nociceptive phenotype, but did not completely reverse it. Furthermore, intrafemorally injected mice presented a profound denervation of the myelomaâbearing bones, a previously unknown feature of the disease. This study reports the intrafemoral inoculation of 5TGM1âGFP cells as a robust immunocompetent model of myelomaâinduced bone pain, with consistent bone loss. Moreover, the data suggest that myelomaâinduced bone pain is caused by a combinatorial mechanism including osteolysis and bone marrow denervation. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research