Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease

作者：Vallet Sonia; Mukherjee Siddhartha; Vaghela Nileshwari; Hideshima Teru; Fulciniti Mariateresa; Pozzi Samantha; Santo Loredana; Cirstea Diana; Patel Kishan; Sohani Aliyah R; Guimaraes Alex; Xie Wanling; Chauhan Dharminder; Schoonmaker Jesse A; Attar Eyal; Churchill Michael; Weller Edie; Munshi Nikhil; Seehra Ja**ir S; Weissleder Ralph; Anderson Kenneth C; Scadden David T; Raje Noopur^*

来源：Proceedings of the National Academy of Sciences, 2010, 107(11): 5124-5129.

DOI：10.1073/pnas.0911929107

• osteoblasts
• osteoclasts
• tumor niche

Understanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-beta family member, as a therapeutically amenable target exploited by multiple myeloma (MM) to alter its microenvironmental niche favoring osteolysis. Increased bone marrow plasma activin A levels were found in MM patients with osteolytic disease. MM cell engagement of marrow stromal cells enhanced activin A secretion via adhesion-mediated JNK activation. Activin A, in turn, inhibited osteoblast differentiation via SMAD2-dependent distalless homeobox-5 down-regulation. Targeting activin A by a soluble decoy receptor reversed osteoblast inhibition, ameliorated MM bone disease, and inhibited tumor growth in an in vivo humanized MM model, setting the stage for testing in human clinical trials.

• 出版日期2010-3-16