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

Abstract

Understanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-β 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.osteoblasts | osteoclasts | tumor niche

Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo

“…This is consistent with previous reports showing activin-A release from osteoblasts. (26,40) However, we cannot exclude the fact that these both ActRIIA.muFc and mab3381 bind other ligands and stimulate osteoblast activity.…”

“…Furthermore, in a recent report, osteoclast numbers in SCID mice bearing INA6 myeloma cells and treated with ActRIIA.muFc also were not significantly different from those in vehicle-treated mice. (40) It is also worthy of note that the effect of human ActRIIA.IgG1.Fc (ACE-011) on bone structure and cells has been studied in cynomolgus monkeys. As with the murine construct, ActRIIA was able to increase bone mass and stimulate bone formation.…”

The role of bone morphogenetic proteins in myeloma cell survival

“…[80] Activin A levels were increased in bone marrow plasma of myeloma patients with osteolytic disease and has been proposed to play an important role in myeloma bone disease, at least in part by inhibiting phosphorylation of SMAD1/5/8 during osteoblastogenesis. [81,82] Lenalidomide treatment has been shown to cause activin A secretion by myeloma BMSC, providing a rationale for a combination treatment of lenalidomide with activin A inhibition. [83] TGF-β is abundant in the bone marrow of myeloma patients, and represses bone formation in osteolytic lesions.…”

Bone Anabolic Agents for the Treatment of Multiple Myeloma

“…Lack of DLX5 gene expression induces abnormal osteogenesis. DLX5 is also a common target of the β-catenin signaling pathway [44,45], so that differential effects on DLX5 transcription account for the opposing effects of Wnt10b, BMP2, TGFβ and activin on OB differentiation [45][46][47]. High activin A levels correlate with advanced ISS stage, extensive bone disease and decreased survival in patients at diagnosis and in the relapse setting.…”

“…Tumor cells do not directly produce activin but stimulate its secretion by BMSC; OCs represent also a source for the cytokine. Activin-mediated upregulation of SMAD2 signaling pathway results in DLX5 inhibition and [47]. In addition, activin exerts a pro-OC effect, stimulating OC differentiation and function [47,49].…”