Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2

Abstract

IntroductionMultiple myeloma (MM) almost exclusively develops and expands in the bone marrow (BM) and generates devastating bone destruction by osteoclasts (OCs). The bone destruction causes debilitating clinical symptoms including intractable bone pain, disabling multiple fractures, and hypercalcemia. The severity of bone disease correlates with the tumor burden and is one of the major parameters in the Durie and Salomon clinical staging system. Furthermore, the aggressive features of MM bone lesions have contributed significantly to its poor prognosis despite the recent development of intensive chemotherapeutic regimens. 1,2 Therefore, elucidation of the molecular mechanism of bone destruction and tumor progression is essential for the development of effective therapies to improve survival as well as quality of life of patients with MM.Interaction between receptor activator of nuclear factor-B (RANK) expressed on the surface of cells of osteoclastic lineage and RANK ligand expressed on stromal cells plays a key role in the development and activation of OCs, whereas osteoprotegerin, a decoy receptor for RANK ligand secreted from stromal cells, inhibits RANK ligand-RANK signaling. 3,4 MM cells stimulate osteoclastogenesis by triggering a coordinated increase in RANK ligand and decrease in osteoprotegerin in the BM. [5][6][7] We and others have demonstrated that osteoclastogenic CC chemokines macrophage inflammatory protein 1␣ (MIP-1␣) and MIP-1␤ are secreted from most MM cells and play a critical role in the development of MM bone lesions. [8][9][10][11][12] These chemokines directly act on MM cells in an autocrine/paracrine fashion and enhance MM cell adhesion to stromal cells through activation of integrins including very late antigen 4. The interaction between MM cells and stromal cells induces RANK ligand expression by stromal cells, leading to OC differentiation and activation. 8 Furthermore, OCs enhance MM cell growth and survival through a cell-to-cell contact-dependent mechanism that is partially mediated by OC-derived interleukin 6 (IL-6) and osteopontin. 13,14 These observations suggest that interactions of MM cells and OCs form a vicious cycle leading to extensive bone destruction and MM cell expansion.Along with enhanced bone resorption, mineralization is impaired in MM bone lesions. Radiographic examinations show radiolucent lesions without calcification known as "punched-out" lesions. Analyses of bone turnover in patients with MM by biochemical bone markers also suggested an imbalance of bone turnover with enhanced bone resorption and suppressed bone formation. 15 However, the mechanisms of impaired bone formation in bone lesions of patients with MM remain poorly understood.A canonical Wingless-type (Wnt) signaling pathway has been shown to play an important role in osteoblast differentiation. Wnts are secreted cysteine-rich glycoproteins, known as regulators of the differentiation of hematopoietic and mesenchymal cells as well as embryonic development. [16][17][18] Wnt proteins bind to the Frizzle...

The role of bone morphogenetic proteins in myeloma cell survival

“…[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. [79] IL-3's bone remodeling effects were shown to depend on increased activin A secretion from CD14 + bone marrow monocytes.…”

Bone Anabolic Agents for the Treatment of Multiple Myeloma

“…Secreted by MM cells as well, they inhibit WNT signaling and OB differentiation. Neutralizing antibodies targeting sFRP2 partially restore OB differentiation in the presence of MM cell conditioned media, thereby sFRP may contribute to OB inhibition [32,39].…”

The pathogenesis of the bone disease of multiple myeloma

“…The treatment of myeloma-bearing SCID-rab mice with anti-Dkk1 antibody reduced osteolytic bone lesions, increased osteoblast number and significantly reduced tumor burden (62). Secreted Frizzled related protein-2 (sFRP-2) is a soluble antagonist of Wnt signaling which has been shown to be expressed by human myeloma cells (63). Furthermore, both exogenous sFRP-2 and myeloma-cell derived sFRP-2 have been shown to play a key role in bone formation in vitro, raising the possibility that sFRP-2 may play a role in the development of myeloma bone disease.…”