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Browsing by Author "Nagata, Yuki"
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Item Acidic microenvironment and bone pain in cancer-colonized bone(SpringerNature, 2015-05-06) Yoneda, Toshiyuki; Hiasa, Masahiro; Nagata, Yuki; Okui, Tatsuo; White, Fletcher A.; Department of Medicine, IU School of MedicineSolid cancers and hematologic cancers frequently colonize bone and induce skeletal-related complications. Bone pain is one of the most common complications associated with cancer colonization in bone and a major cause of increased morbidity and diminished quality of life, leading to poor survival in cancer patients. Although the mechanisms responsible for cancer-associated bone pain (CABP) are poorly understood, it is likely that complex interactions among cancer cells, bone cells and peripheral nerve cells contribute to the pathophysiology of CABP. Clinical observations that specific inhibitors of osteoclasts reduce CABP indicate a critical role of osteoclasts. Osteoclasts are proton-secreting cells and acidify extracellular bone microenvironment. Cancer cell-colonized bone also releases proton/lactate to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Thus, extracellular microenvironment of cancer-colonized bone is acidic. Acidosis is algogenic for nociceptive sensory neurons. The bone is densely innervated by the sensory neurons that express acid-sensing nociceptors. Collectively, CABP is evoked by the activation of these nociceptors on the sensory neurons innervating bone by the acidic extracellular microenvironment created by bone-resorbing osteoclasts and bone-colonizing cancer cells. As current treatments do not satisfactorily control CABP and can elicit serious side effects, new therapeutic interventions are needed to manage CABP. Understanding of the cellular and molecular mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and by which the expression and function of the acid-sensing nociceptors on the sensory neurons are regulated would facilitate to develop novel therapeutic approaches for the management of CABP.Item Contribution of acidic extracellular microenvironment of cancer-colonized bone to bone pain(Elsevier, 2015-10) Yoneda, Toshiyuki; Hiasa, Masahiro; Nagata, Yuki; Okui, Tatsuo; White, Fletcher; Department of Medicine, IU School of MedicineSolid and hematologic cancer colonized bone produces a number of pathologies. One of the most common complications is bone pain. Cancer-associated bone pain (CABP) is a major cause of increased morbidity and diminishes the quality of life and affects survival. Current treatments do not satisfactorily control CABP and can elicit adverse effects. Thus, new therapeutic interventions are needed to manage CABP. However, the mechanisms responsible for CABP are poorly understood. The observation that specific osteoclast inhibitors can reduce CABP in patients indicates a critical role of osteoclasts in the pathophysiology of CABP. Osteoclasts create an acidic extracellular microenvironment by secretion of protons via vacuolar proton pumps during bone resorption. In addition, bone-colonized cancer cells also release protons and lactate via plasma membrane pH regulators to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Since acidosis is algogenic for sensory neurons and bone is densely innervated by sensory neurons that express acid-sensing nociceptors, the acidic bone microenvironments can evoke CABP. Understanding of the mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and the expression and function of the acid-sensing nociceptors are regulated should facilitate the development of novel approaches for management of CABP. Here, the contribution of the acidic microenvironment created in cancer-colonized bone to elicitation of CABP and potential therapeutic implications of blocking the development and recognition of acidic microenvironment will be described. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.Item Increased S1P expression in osteoclasts enhances bone formation in an animal model of Paget's disease(Wiley, 2021-04) Nagata, Yuki; Miyagawa, Kazuaki; Ohata, Yasuhisa; Petrusca, Daniela N.; Pagnotti, Gabriel M.; Mohammad, Khalid S.; Guise, Theresa A.; Windle, Jolene J.; Roodman, G. David; Kurihara, Noriyoshi; Medicine, School of MedicinePaget's disease (PD) is characterized by increased numbers of abnormal osteoclasts (OCLs) that drive exuberant bone formation, but the mechanisms responsible for the increased bone formation remain unclear. We previously reported that OCLs from 70% of PD patients express measles virus nucleocapsid protein (MVNP), and that transgenic mice with targeted expression of MVNP in OCLs (MVNP mice) develop bone lesions and abnormal OCLs characteristic of PD. In this report, we examined if OCL-derived sphingosine-1-phosphate (S1P) contributed to the abnormal bone formation in PD, since OCL-derived S1P can act as a coupling factor to increase normal bone formation via binding S1P-receptor-3 (S1PR3) on osteoblasts (OBs). We report that OCLs from MVNP mice and PD patients expressed high levels of sphingosine kinase-1 (SphK-1) compared with wild-type (WT) mouse and normal donor OCLs. SphK-1 production by MVNP-OCLs was interleukin-6 (IL-6)-dependent since OCLs from MVNP/IL-6-/- mice expressed lower levels of SphK-1. Immunohistochemistry of bone biopsies from a normal donor, a PD patient, WT and MVNP mice confirmed increased expression levels of SphK-1 in OCLs and S1PR3 in OBs of the PD patient and MVNP mice compared with normal donor and WT mice. Further, MVNP-OCLs cocultured with OBs from MVNP or WT mice increased OB-S1PR3 expression and enhanced expression of OB differentiation markers in MVNP-OBs precursors compared with WT-OBs, which was mediated by IL-6 and insulin-like growth factor 1 secreted by MVNP-OCLs. Finally, the addition of an S1PR3 antagonist (VPC23019) to WT or MVNP-OBs treated with WT and MVNP-OCL-conditioned media (CM) blocked enhanced OB differentiation of MVNP-OBs treated with MVNP-OCL-CM. In contrast, the addition of the SIPR3 agonist, VPC24191, to the cultures enhanced osterix and Col-1A expression in MVNP-OBs treated with MVNP-OCL-CM compared with WT-OBs treated with WT-OCL-CM. These results suggest that IL-6 produced by PD-OCLs increases S1P in OCLs and S1PR3 on OBs, to increase bone formation in PD.