Bone Abstracts

Multiple myeloma is usually incurable, the bone marrow niche providing a protective microenvironment for quiescent tumour cells. We hypothesised that manipulation of BMP activity, a regulator of cell differentiation in the bone marrow, might affect control of tumour growth by its niche and in addition alter the lytic bone disease of myeloma. Moreover BMP signalling contributes to the hepcidin upregulation and resultant inflammatory anaemia that is characteristic of myeloma. Regulation of BMP signalling within the myeloma bone marrow microenvironment was investigated in vitro and in vivo. In myeloma-bearing KaLwRij/5TGM1 mouse model, the BMP signalling inhibitor LDN-193189 (LDN) significantly improved bone volume (P=0.003) and reduced serum TRAP levels (P=0.003). LDN had no effect on overall tumour burden, however altered the niche-preference (endosteal vs. central marrow) of myeloma cells to favour the endosteal niche, reported to house the dormant clonal fraction (ratio endosteal: central marrow myeloma distribution 0.23 vehicle group, 0.37 LDN group, P=0.034). In early disease, serum hepcidin correlated with disease burden (r²=0.55 P=0·03), and was partly normalised by LDN. Tumour BMP signalling activity, measured by expression of BMP response genes id1 and smad6, increased tenfold when myeloma cell lines were cultured in contact with bone marrow stromal cells. This effect was abrogated by LDN. Expression of rankl was decreased by LDN in stromal cells from myeloma-bearing mice (P=0.03). In summary, BMP inhibition improves myeloma bone disease potentially by reducing RANKL levels thereby reducing osteoclast activity. The additional benefit of hepcidin reduction could alleviate the inflammatory anaemia of myeloma. If LDN also alters niche preference in favour of endosteal-sited dormancy, it could have use in prolongation of quiescent phases, e.g. MGUS and post-treatment remission. Taken together, our results demonstrate the potential for inhibition of BMP signalling for the treatment of myeloma and the associated bone disease.