Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease
| Autor: | Gooding, S, Olechnowicz, S, Morris, E, Armitage, A, Arezes, J, Frost, J, Repapi, E, Edwards, J, Ashley, N, Waugh, C, Gray, N, Martinez-Hackert, Lim, PJ, Pasricha, S-R, Knowles, H, Mead, A, Ramasamy, K, Drakesmith, A, Edwards, C |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Cancer microenvironment
Science Osteoclasts Mice Inbred Strains Myeloma Article Mice Bone Density Bone Marrow Osteogenesis Cell Line Tumor hemic and lymphatic diseases Animals Humans Femur RNA-Seq Bone lcsh:Science Adaptor Proteins Signal Transducing Tibia Gene Expression Profiling Stem Cells Bone Morphogenetic Protein Receptors Xenograft Model Antitumor Assays Disease Models Animal Pyrimidines Treatment Outcome Gene Expression Regulation Bone Morphogenetic Proteins Pyrazoles lcsh:Q Bone Diseases Multiple Myeloma Injections Intraperitoneal Signal Transduction |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-15 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-12296-1 |
| Popis: | Multiple myeloma is an incurable, bone marrow-dwelling malignancy that disrupts bone homeostasis causing skeletal damage and pain. Mechanisms underlying myeloma-induced bone destruction are poorly understood and current therapies do not restore lost bone mass. Using transcriptomic profiling of isolated bone lining cell subtypes from a murine myeloma model, we find that bone morphogenetic protein (BMP) signalling is upregulated in stromal progenitor cells. BMP signalling has not previously been reported to be dysregulated in myeloma bone disease. Inhibition of BMP signalling in vivo using either a small molecule BMP receptor antagonist or a solubilized BMPR1a-FC receptor ligand trap prevents trabecular and cortical bone volume loss caused by myeloma, without increasing tumour burden. BMP inhibition directly reduces osteoclastogenesis, increases osteoblasts and bone formation, and suppresses bone marrow sclerostin levels. In summary we describe a novel role for the BMP pathway in myeloma-induced bone disease that can be therapeutically targeted. Multiple myeloma is a cancer of the bone marrow that can induce bone disease. Here, the authors profile the transcriptome of bone-lining cells and find a targetable role of bone morphogenetic protein (BMP) signalling in myeloma-induced bone-disease |
| Databáze: | OpenAIRE |
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