Myeloma cells suppress osteoblasts through sclerostin secretion

Abstract

Wingless-type (Wnt) signaling through the secretion of Wnt inhibitors Dickkopf1, soluble frizzled-related protein-2 and -3 has a key role in the decreased osteoblast (OB) activity associated with multiple myeloma (MM) bone disease. We provide evidence that another Wnt antagonist, sclerostin, an osteocyte-expressed negative regulator of bone formation, is expressed by myeloma cells, that is, human myeloma cell lines (HMCLs) and plasma cells (CD138+ cells) obtained from the bone marrow (BM) of a large number of MM patients with bone disease. We demonstrated that BM stromal cells (BMSCs), differentiated into OBs and co-cultured with HMCLs showed, compared with BMSCs alone, reduced expression of major osteoblastic-specific proteins, decreased mineralized nodule formation and attenuated the expression of members of the activator protein 1 transcription factor family (Fra-1, Fra-2 and Jun-D). Moreover, in the same co-culture system, the addition of neutralizing anti-sclerostin antibodies restored OB functions by inducing nuclear accumulation of β-catenin. We further demonstrated that the upregulation of receptor activator of nuclear factor κ-B ligand and the downregulation of osteoprotegerin in OBs were also sclerostin mediated. Our data indicated that sclerostin secretion by myeloma cells contribute to the suppression of bone formation in the osteolytic bone disease associated to MM.

A Review of Osteocyte Function and the Emerging Importance of Sclerostin

“…Myeloma cells release RANKL and inhibit production of as well as induce degradation of OPG 90 . Additional studies have revealed that myeloma cells also suppress osteoblasts by secreting sclerostin 91 . A positive correlation between severity of bone disease and circulating levels of serum sclerostin suggests multiple myeloma cells utilize sclerostin in the formation of osteolytic lesions 92 .…”

The role of bone morphogenetic proteins in myeloma cell survival

“…[33] Sclerostin is expressed by osteocytes but can also be expressed by myeloma cells and high serum levels in myeloma patients correlated with advanced disease stage. [76,77] Another Wnt inhibitor, sFRP-2, is secreted by myeloma cells and suppresses bone formation. [78] Myeloma cells may secrete interleukin (IL)-3, and IL-3 from the bone marrow plasma of myeloma patients inhibited both basal and BMP-2 induced osteoblast formation.…”

Bone Anabolic Agents for the Treatment of Multiple Myeloma

“…MM-derived sclerostin inhibits osteoblastogenesis presumably via suppression of β-catenin signaling, since neutralizing antibodies lead to intranuclear β-catenin accumulation and ultimately restore OB differentiation in the presence of MM cells. In addition, sclerostin deregulates the RANKL/OPG balance [38]. Sclerostin may therefore play an important role in MM-mediated OB inhibition.…”

“…Similarly, sclerostin inhibition in cynomolgus monkeys increases bone mineral density up to 30% [98]. In MM, neutralizing antibodies against sclerostin overcome MM-induced OB inhibition via accumulation of nuclear β-catenin [38]. AMG785 (Amgen) is an anti-sclerostin antibody assessed in a phase I randomized, double-blind, placebo-controlled, ascending, single-dose trial in 72 healthy men and postmenopausal women.…”