Bone morphogenetic protein-4 inhibits proliferation and induces apoptosis of multiple myeloma cells

Abstract

Bone morphogenetic proteins (BMPs) can be isolated from organic bone matrix and are able to initiate de novo cartilage and bone formation. Here it is shown that BMP-4 inhibited DNA synthesis in a dosedependent manner in 3 IL-6-dependent multiple myeloma (MM) cell lines (OH-2, IH-1, and ANBL-6). In contrast, no effect on DNA synthesis was observed in 3 IL-6-independent MM cell lines ( IntroductionMultiple myeloma (MM) is a B-cell malignancy characterized by a low-grade proliferation of plasma cells in the bone marrow. Tumor progression is frequently accompanied by osteolysis caused by increased bone resorption and decreased bone formation. In vitro, myeloma cells can be responsive to several cytokines with proliferative and anti-apoptotic effects, of which IL-6 is the most important. 1,2 Few cytokines with the ability to induce apoptosis or to inhibit proliferation of myeloma cells have been identified. Interferon (IFN)-␥ inhibits IL-6-dependent proliferation of myeloma cell lines and patient samples. 3,4 In vitro effects of IFN-␣ are more complex because induction of proliferation, increased survival, and inhibition of proliferation have been reported. 2 IFN-␣ treatment of patients with MM may prolong the plateau phase, but it does not significantly prolong survival. 5,6 IFN-␥ was evaluated in one small clinical trial and showed no beneficial effect. 7 Activin A, a member of the transforming growth factor (TGF)-␤ superfamily, induces apoptosis and inhibits proliferation in murine plasmacytoma. [8][9][10][11] In addition, Fas ligand (FasL) and TRAIL (Apo-2 ligand) may induce apoptosis in some myeloma cells. 12,13 Bone morphogenetic proteins (BMPs) are members of the TGF-␤ superfamily and were originally identified by their unique ability to induce ectopic cartilage and bone formation in vivo. 14,15 To date, at least 15 BMPs have been characterized. 16 In bone, osteoblasts and chondrocytes synthesize BMPs, and these proteins play important roles in bone formation and bone cell differentiation by stimulating alkaline phosphatase activity and synthesis of proteoglycan, collagen, and osteocalcin. 17,18 BMPs also induce osteoblast differentiation of uncommitted bone marrow stromal precursor cells and are involved in postnatal bone remodeling. 19,20 Furthermore, in animal models, BMPs promote the healing of large segmental fractures and bone defects. 16,21 BMPs and their receptors are expressed in tissues other than bone, and it has been demonstrated that BMPs play multiple roles in the regulation of growth, differentiation, and apoptosis of various cell types. This may be exemplified by the essential role of BMP-4 in ventralization of the embryo. [22][23][24] In malignant disease, BMPs modulate cell proliferation, frequently in an inhibitory manner, and have been implicated in the osteosclerotic pattern of prostate cancer bone metastasis. [25][26][27][28][29] Recently, BMPs have emerged as proteins of significance in hematology. BMP-4 strictly controls the formation of the ventral hematopoietic islands in Xenopus emb...

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

“…We have recently demonstrated the inhibitory effect of BMP-6 on immature as well as mature cells of B cell origin [16,17]. Similar effects were demonstrated for BMP-2, BMP-4, BMP-6 and BMP-7 in human myeloma cells [18,19]. Several studies have shown that BMP signalling may play a role in thymocyte differentiation.…”

“…However, we recently showed that BMP-6 inhibits growth of human B progenitors and mature B cells [16,17]. In multiple myeloma cells, BMP-2, BMP-4, BMP-6 and BMP-7 have been shown to have antiproliferative and proapoptotic effects [18,19]. Interestingly, BMP-2 and BMP-4 were shown to inhibit early thymocyte differentiation [20], whereas transgenic expression of the BMP antagonist Noggin implicated that BMP signalling was required for normal thymus development [21].…”

Bone morphogenetic proteins induce apoptosis in multiple myeloma cells by Smad-dependent repression of MYC

“…Apoptosis, as detected by annexin-V staining, cannot be detected in the cultures before B20 h after BMP addition in this cell line. 14 However, when mRNA levels were analyzed 8 h after cytokine addition, 823 probe sets were significantly different in cells treated with BMP-4 compared with untreated cells, that is, in cells later going to die by apoptosis versus in surviving cells (data not shown).…”

Bone morphogenetic protein-5, -6 and -7 inhibit growth and induce apoptosis in human myeloma cells

“…Provided this is also the case for myeloma cells, it may explain why the tumor-suppressive effect of TGF-b is generally weak in multiple myeloma (Urashima et al, 1996). As shown by our group earlier, BMP-4 inhibits proliferation and induces apoptosis in some myeloma cell lines and in freshly harvested myeloma cells (Hjertner et al, 2001). However, several cell lines, as well as occasional primary myeloma cell samples, are resistant to BMP-4 treatment.…”