Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.