RANK-Fc: a therapeutic antagonist for RANK-L in myeloma. Review uri icon

Overview

MeSH

  • Animals
  • Disease Models, Animal
  • Disease Progression
  • Humans
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Mice
  • Mice, SCID
  • Osteoprotegerin
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Tumor Necrosis Factor

MeSH Major

  • Carrier Proteins
  • Glycoproteins
  • Membrane Glycoproteins
  • Multiple Myeloma
  • Osteoclasts
  • Receptors, Cytoplasmic and Nuclear

abstract

  • Severe bone destruction due to inappropriate osteoclastogenesis is a prominent feature of multiple myeloma (MM). MM increases bone loss by disrupting the checks that normally control signaling by receptor activator of nuclear factor kappaB ligand (RANK-L, also called TRANCE [tumor necrosis factor-related, activation-induced cytokine], osteoprotegerin ligand [OPG-L], osteoclast differentiation factor [ODF], and tumor necrosis factor superfamily member 11 [TNFSF11]), a TNF-family cytokine required for osteoclast differentiation and activation. RANK-L binds to its functional receptor RANK (TNF receptor superfamily member 11a [TNF RSF11a]) to stimulate osteoclastogenesis. Osteotropic cytokines regulate this process by controlling bone marrow stromal expression of RANK-L. Further control over osteoclastogenesis is maintained by regulated expression of osteoprotegerin (OPG, also called osteoclastogenesis inhibitory factor and TNFRSF11b), a soluble decoy receptor for RANK-L. In normal bone marrow, abundant stores of OPG in stroma, megakaryocytes, and myeloid cells provide a natural buffer against increased RANK-L. MM disrupts these controls by increasing expression of RANK-L and decreasing expression of OPG. Concurrent deregulation of RANK-L and OPG expression is found in bone marrow biopsies from patients with MM but not in specimens from patients with non-MM hematologic malignancies. RANK-Fc is a recombinant RANK-L antagonist that is formed by fusing the extracellular domain of RANK to the Fc portion of human immunoglobulin G(1) (hIgG(1)). In vitro, addition of RANK-Fc virtually eliminates the formation of osteoclasts in cocultures of MM with bone marrow and osteoblast/stromal cells. The severe combined immunodeficiency (SCID)/ARH77 mouse model and the SCID-hu-MM mouse model of human MM were used to assess the ability of RANK-Fc to block the development of MM-induced bone disease in vivo. Mice received either RANK-Fc or hIgG(1) 200 microg intravenously three times per week. RANK-Fc limited bone destruction in both the SCID/ARH-77 model and the SCID-hu-MM model. Administration of RANK-Fc also caused a marked reduction in tumor burden and serum paraprotein in SCID-hu-MM mice that was associated with the restoration of OPG and a reduction in RANK-L expression in the xenograft. MM-induced bone destruction requires increased RANK-L expression and is facilitated by a concurrent reduction in OPG, a natural decoy receptor for RANK-L. Administration of the RANK-L antagonist RANK-Fc limits MM-induced osteoclastogenesis, development of bone disease, and MM tumor progression. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11134

publication date

  • February 1, 2003

has subject area

  • Animals
  • Carrier Proteins
  • Disease Models, Animal
  • Disease Progression
  • Glycoproteins
  • Humans
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Membrane Glycoproteins
  • Mice
  • Mice, SCID
  • Multiple Myeloma
  • Osteoclasts
  • Osteoprotegerin
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Tumor Necrosis Factor

Research

keywords

  • Journal Article
  • Review

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1002/cncr.11134

PubMed ID

  • 12548579

Additional Document Info

start page

  • 802

end page

  • 812

volume

  • 97

number

  • 3 Suppl