| Popis: |
Multiple myeloma is an incurable, bone marrow-dwelling malignancy of terminally differentiated plasma cells. It disrupts bone homeostasis causing lytic lesions, skeletal damage and pain. Mechanisms underlying myeloma-induced bone destruction are poorly understood and current therapies do not restore lost bone mass. In this project, I performed transcriptomic profiling of isolated endosteal cell types from a murine myeloma model, which had not previously been described. I found bone morphogenetic protein (BMP) signalling to be upregulated in mesenchymal progenitor cells of the bone lining niche in myeloma-bearing mice. BMP signalling is not previously reported to be dysregulated in myeloma bone disease. Inhibition of BMP signalling in vivo using either a small molecule Type 1 BMP receptor antagonist (LDN193189) or a solubilized Alk3-Fc (Bmpr1a-Fc) receptor ligand trap prevented trabecular and cortical bone volume loss caused by myeloma, without altering tumour burden. These inhibitors directly reduced osteoclast formation and activity, increased osteoblast number and new bone formation, and suppressed bone marrow levels of sclerostin, a Wnt inhibitor implicated in mediating the failure of bone repair in myeloma sufferers. Conversely, specific blockade of BMP6 in myeloma-bearing mice decreased levels of the iron regulatory hormone hepcidin and improved iron availability and haemoglobin, but did not alter bone disease or tumour burden, indicating this myeloma-expressed BMP is not responsible for altered bone homeostasis. In summary this work describes a novel technique in the investigation of myeloma-niche interactions, shows its use in revealing a novel pathway involved in the pathogenesis of myeloma bone disease, and demonstrates that the therapeutic targeting of the BMP pathway has both anti-resorptive and anabolic benefits to bone metabolism, which could have a role alongside anti-tumour treatments. |
