A viable model of bone cancer has been developed in which lytic sarcoma cells are injected into the intramedullary space of the mouse femur. The cells are confined within the bone by an amalgam plug produce extensive bone destruction and pain behaviors similar to that observed in patients with bone cancer. A breast cancer cell line bone pain model will also be developed. With these models the cellular and neurochemical pathophysiology that generates and maintains cancer-induced bone pain can be studied. These studies are proposed to define the distribution and time course of tumor invasion in bone, tumor angiogenesis, osteoclast proliferation, bone destruction, remodeling and bone cancer nociceptive behaviors (Aim 1). The studies will define sensory and sympathetic innervation of bone as the interosseus mass grows and nociceptive state changes assessing tumor growth and bone destruction (Aim 2). Neurochemical changes in the spinal cord, dorsal column nuclei, and sympathetic and dorsal root ganglia will be monitored (Aim 3). Pharmacological manipulation of the generation and maintenance of bone cancer nociceptive events will be attempted (Aim 4). The information generated by these studies should significantly expand our understanding of the cellular and molecular mechanisms involved in the generation of bone cancer pain and may lead to effective therapies for treating bone cancer pain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-IFCN-4 (03))
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Porter, Linda L
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University of Minnesota Twin Cities
Engineering (All Types)
Schools of Dentistry
United States
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Chartier, Stephane R; Mitchell, Stefanie A T; Majuta, Lisa A et al. (2018) The Changing Sensory and Sympathetic Innervation of the Young, Adult and Aging Mouse Femur. Neuroscience 387:178-190
Majuta, Lisa A; Mitchell, Stefanie A T; Kuskowski, Michael A et al. (2018) Anti-nerve growth factor does not change physical activity in normal young or aging mice but does increase activity in mice with skeletal pain. Pain 159:2285-2295
Majuta, Lisa A; Guedon, Jean-Marc G; Mitchell, Stefanie A T et al. (2017) Anti-nerve growth factor therapy increases spontaneous day/night activity in mice with orthopedic surgery-induced pain. Pain 158:605-617
Guedon, Jean-Marc G; Longo, Geraldine; Majuta, Lisa A et al. (2016) Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain. Pain 157:1239-47
Thompson, Michelle L; Jimenez-Andrade, Juan Miguel; Mantyh, Patrick W (2016) Sclerostin Immunoreactivity Increases in Cortical Bone Osteocytes and Decreases in Articular Cartilage Chondrocytes in Aging Mice. J Histochem Cytochem 64:179-89
Thompson, Michelle L; Jimenez-Andrade, Juan M; Chartier, Stephane et al. (2015) Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer. Pain 156:1692-702
Majuta, Lisa A; Longo, Geraldine; Fealk, Michelle N et al. (2015) Orthopedic surgery and bone fracture pain are both significantly attenuated by sustained blockade of nerve growth factor. Pain 156:157-65
Mantyh, Patrick W (2014) Bone cancer pain: from mechanism to therapy. Curr Opin Support Palliat Care 8:83-90
McCaffrey, Gwen; Thompson, Michelle L; Majuta, Lisa et al. (2014) NGF blockade at early times during bone cancer development attenuates bone destruction and increases limb use. Cancer Res 74:7014-23
Mantyh, Patrick W (2014) The neurobiology of skeletal pain. Eur J Neurosci 39:508-19

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