Elsevier

Bone

Volume 48, Issue 1, 1 January 2011, Pages 129-134
Bone

Review
TGF-β-related mechanisms of bone destruction in multiple myeloma

https://doi.org/10.1016/j.bone.2010.05.036Get rights and content

Abstract

In destructive bone lesions of multiple myeloma (MM), osteoclastic bone resorption is enhanced, while bone formation is suppressed with impaired osteoblast differentiation from their progenitor cells. As a result, a strong negative balance in bone turnover develops in MM bone lesions. The suppression of bone formation is mainly due to a secretion of Wnt signal inhibitors, secreted Frizzled-related protein (sFRP)-2 and 3 and dikkopf1 (DKK1). In addition, the enhanced bone resorption in MM bone lesions causes a marked increase in the release and activation of transforming growth factor (TGF)-β. Although TGF-β enhances the recruitment and proliferation of osteoblast progenitors, TGF-β potently inhibits later phases of osteoblast differentiation and maturation and suppresses matrix mineralization. Thus, TGF-β also plays a role in the suppression of bone formation in MM bone lesions. In fact, when TGF-β action is suppressed by inhibitors of TGF-β type I receptor kinase, the inhibition of terminal differentiation of osteoblasts and mineralization is abrogated. While immature mesenchymal stromal cells support the growth and survival of MM cells, mature osteoblasts enhance MM cell apoptosis and cell cycle arrest. Thus, the inhibition of TGF-β signaling by TGF-β type I receptor kinase inhibitor causes not only an enhancement of bone formation but also a suppression of MM cell growth. Inhibition of TGF-β signaling can become a new therapeutic approach against MM.

Section snippets

Myeloma cells enhance bone resorption and suppress bone formation

Multiple myeloma (MM) expands almost exclusively in the bone marrow and generates devastating bone lesions. In typical destructive bone lesions of MM, osteoclastic bone resorption is enhanced with an impairment of bone formation. MM cells enhance osteoclastogenesis by a secretion of C–C chemokines, macrophage inflammatory protein (MIP)-1α and β [1], [2], [3]. As a result, MM creates a microenvironment rich in receptor activator of nuclear factor-kappaB ligand (RANKL), with deficient

Secretion of Wnt inhibitors by myeloma cells

In an effort to find out factors that suppress osteoblastic bone formation, Tian et al. [19] performed oligonucleotide microarray profiling and identified dickkopf1 (DKK1) as an inhibitor of OB differentiation secreted by MM cells. DKK1 is an inhibitor of canonical Wingless-type (Wnt) signaling pathway that has been shown to play an important role in OB differentiation. DKK1 binds to LDL-related protein 5 (LRP5), which serves as a coreceptor with Frizzled for Wnt and inhibits canonical Wnt

TGF-β suppresses bone formation

In addition to the Wnt inhibitors, there is another important inhibitor of OB differentiation and bone formation. Although many in vitro experiments demonstrated that transforming growth factor (TGF)-β enhances the recruitment and proliferation of OB progenitors and promotes matrix protein synthesis [23], TGF-β potently inhibits later phases of OB differentiation and maturation to suppress matrix mineralization [24], [25], [26]. Thus, TGF-β enhances the premature OB cell pool and matrix protein

TGF-β is deposited in bone matrix, released, and activated by bone resorption

TGF-β family consists of three isoforms, TGF-β1, -β2, and -β3 with high sequence homology. Among them, TGF-β1 is the most abundant isoform in bone, and bone contains about 200 μg/kg TGF-β1 [29], which is the second largest source to platelets in the body [30]. TGF-β1 is synthesized in OBs as a protein with three portions; the signal peptide with 29 amino acids, the latency-associated peptide (LAP) with 249 amino acids, and the mature peptide with 112 amino acids. The signal peptide is cleaved in

TGF-β signal is suppressed in malignant cells including myeloma cells

Although TGF-β inhibits proliferation of various cells, hematologic and other malignant cells including MM cells evade TGF-β signaling and maintain proliferation even in the presence of TGF-β. Various abnormalities in the constituents of TGF-β signaling pathway in malignant cells have been reported, including mutation, deletion, and disruption by oncoproteins of members of the TGF-β signaling pathway [35], [36]. TGF-β signal is transduced through type I and type II serine/threonine kinase

TGF-β inhibition enhances osteoblast differentiation

MM cells secrete Wnt inhibitors, sFRP-2 and 3 and DKK1, and enhance the release and activation of TGF-β from the bone matrix, both of which contribute to the suppression of OB differentiation and bone formation by MM. Therefore, enhancement of Wnt signaling or inhibition of TGF-β signaling may reverse the suppression of OB differentiation and bone formation. However, Wnt/β-catenin signaling is shown to be involved in cell cycle regulation, proliferation, and invasion of MM cells, contributing

Mature osteoblasts suppress myeloma cell growth and survival

Because MM cells suppress OB differentiation, immature OBs/stromal cells that support the survival and growth of MM cells surround MM cells. A recent report demonstrates that these mesenchymal stromal cells show distinct transcriptional profiles from OBs [52]. Thus, there was a question whether differentiation of mesenchymal stromal cells into mature OBs affects the growth/survival-promoting activity of stromal cells on MM cells. We examined MM cell growth and survival in cocultures with bone

Enhancement of osteoblast maturation by TGF-β inhibition suppresses myeloma growth

Because TGF-β inhibition reverses the suppression of terminal OB differentiation, and mature OBs suppress MM cell proliferation, there is a possibility that inhibition of TGF-β action in MM bone lesions may suppress MM cell growth. To examine such a possibility, an in vivo mice model was utilized in which an IL-6 or stromal cell-dependent human MM cell line, INA6, was inoculated directly into the bone marrow cavity of rabbit bones implanted subcutaneously to SCID mice (SCID-rab model) [54].

Conclusions

Suppression of OB differentiation plays an important role in the formation of devastating destructive lesions in the bone of MM patients. In addition to the bone lesions, because mature OBs inhibit the growth and survival of MM cells, the suppression of OB differentiation creates an environment suitable for MM growth. MM cells inhibit OB differentiation by secreting Wnt signal inhibitors, DKK1 and sFRP-2. However, Wnt signal enhances MM growth, and an approach to counteract Wnt inhibitors may

References (54)

  • T. Oshima et al.

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

    Blood

    (2005)
  • Y. Takeuchi et al.

    Differentiation and cell surface expression of transforming growth factor-beta receptors are regulated by interaction with matrix collagen in murine osteoblastic cells

    J Biol Chem

    (1996)
  • R.K. Assoian et al.

    Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization

    J Biol Chem

    (1983)
  • D.B. Rifkin

    Latent transforming growth factor-beta (TGF-beta) binding proteins: orchestrators of TGF-beta availability

    J Biol Chem

    (2005)
  • S.L. Dallas et al.

    Characterization and autoregulation of latent transforming growth factor beta (TGF beta) complexes in osteoblast-like cell lines. Production of a latent complex lacking the latent TGF beta-binding protein

    J Biol Chem

    (1994)
  • M. Dong et al.

    Role of transforming growth factor-beta in hematologic malignancies

    Blood

    (2006)
  • Y. Shi et al.

    Mechanisms of TGF-beta signaling from cell membrane to the nucleus

    Cell

    (2003)
  • A. Nakano et al.

    Pin1 down-regulates transforming growth factor-beta (TGF-beta) signaling by inducing degradation of Smad proteins

    J Biol Chem

    (2009)
  • N. Franchimont et al.

    Transforming growth factor-beta increases interleukin-6 transcripts in osteoblasts

    Bone

    (2000)
  • J. Dutta-Simmons et al.

    Aurora kinase A is a target of Wnt/beta-catenin involved in multiple myeloma disease progression

    Blood

    (2009)
  • M. Fulciniti et al.

    Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma

    Blood

    (2009)
  • K. Todoerti et al.

    Distinct transcriptional profiles characterize bone microenvironment mesenchymal cells rather than osteoblasts in relationship with multiple myeloma bone disease

    Exp Hematol

    (2010)
  • J.S. Damiano et al.

    Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines

    Blood

    (1999)
  • S.J. Choi et al.

    Antisense inhibition of macrophage inflammatory protein 1-alpha blocks bone destruction in a model of myeloma bone disease

    J Clin Invest

    (2001)
  • R.N. Pearse et al.

    Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression

    Proc Natl Acad Sci U S A

    (2001)
  • M. Abe et al.

    BAFF and APRIL as osteoclast-derived survival factors for myeloma cells: a rationale for TACI-Fc treatment in patients with multiple myeloma

    Leukemia

    (2006)
  • R. Soldi et al.

    Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2

    EMBO J

    (1999)
  • Cited by (0)

    View full text