ECTS Abstracts (2015) 1 CABSOC1.5

The pain mediator NGF is induced by multiple myeloma in vivo, and relieved by therapeutic activation of adiponectin signalling

Sam Olechnowicz, Megan Weivoda, Szi Kay Leung, Seint Lwin, James Edwards & Claire Edwards

University of Oxford, Oxford, UK.

Multiple myeloma (MM) is a plasma cell neoplasm which causes osteolytic bone disease, and at diagnosis the most common symptom is bone pain. Adiponectin (Adpn) is a myeloma-suppressive adipokine which negatively correlates with the major pain mediator nerve growth factor (NGF) in osteoarthritis. We sought to determine whether NGF was increased in MM and the mechanism of NGF regulation within the MM-bone microenvironment. Mice were inoculated with 5TGM1-MM cells and tumour burden was associated with a significant increase in serum NGF (P<0.01). Immunohistochemistry revealed NGF expression in stromal cells within the growth plate, while CGRP+ nerves were detectable in the nearby periosteum. 5TGM1-MM or RPMI-8226 human MM cells did not express NGF, while cells found within bone (2T3 osteoblasts, ST2 bone marrow stromal cells (BMSCs), HS5 BMSCs, and ATDC5 chondrocytic cells) expressed high NGF. Coculture of MM cells with BMSCs or osteoblasts significantly increased NGF expression in BMSCs or osteoblasts (P<0.05). MM-derived cytokines such as TNFα up-regulated NGF in 2T3 cells, ATDC5 chodrocytes and HS5 BMSCs (P<0.05). Adpn inhibited an LPS-induced increase in NGF in 2T3 osteoblasts and blockade of Adpn signalling by siRNA towards Adpn receptors AdipoR1 or AdipoR2 resulted in a significant twofold increase in NGF, which was further increased upon combination with TNFα. The Adpn-inducer L-4F was compared with bortezomib and melphalan in vivo in 5TGM1MM-bearing mice. All treatments gave a similar reduction in tumour burden (L-4F; 36%, bortezomib; 34%, melphalan; 36%, P<0.01), yet only L-4F induced a significant twofold reduction in serum NGF induction (P<0.01). Our results demonstrate that NGF is increased in MM in vivo, likely due to MM-induced up-regulation of stromal NGF. NGF is likely to be a cause of MM-induced bone pain, therefore Adpn-targeted therapies may provide an improvement over traditional approaches by reducing tumour burden while also acting to inhibit bone pain.

Disclosure: The authors declared no competing interests. This work was supported by the NIH/NCI (R01 CA137116) and Leukaemia and Lymphoma Research (UK).

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