In 1991, Bataille et al
(Bataille et al, 1991
) originally reported that increased osteoblast activity coupled with increased bone resorption rate synchronically occur early in conversion from the benign precursor condition (monoclonal gammopathy of undetermined significance, MGUS) to overt MM and that patients who maintained high osteoblast activity did not develop osteolytic disease. MSCs isolated from BM of patients with MM are genetically and phenotypically abnormal and have impaired osteogenic potential (Corre et al, 2007
; Garayoa et al, 2009
; Wallace et al, 2001
). In addition, myeloma cells actively suppress osteoblastogenesis through direct cell–cell contact and production of soluble factors. Co-culturing myeloma cells with osteoblasts resulted in downregulation of the osteoblast marker, osteocalcin (Barille et al, 1995
), and direct contact between myeloma cells and MSCs, mediated by cell-surface molecules very late antigen 4 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1), resulted in MSCs downregulating expression of the critical osteoblast transcription factor Runt-related transcription factor 2 (RUNX2). These reports are in accord with histopathological analyses indicating that osteolytic lesions in MM often occur adjacent to the tumour area (Roodman, 2004
It is now evident also that osteoblast differentiation is inhibited by factors secreted by myeloma cells (e.g.
, Wnt-signaling inhibitors DKK1 [Tian et al, 2003
] and secreted frizzled-related protein-2 [Oshima et al, 2005
], IL-7 [Giuliani et al, 2005b
], and hepatocyte growth factor (HGF) [Standal et al, 2007
]) and by microenvironmental cells within myelomatous bone (e.g.
, IL-3 [Lee et al, 2004
; Ehrlich et al, 2005
]). Importantly, expression or circulating levels of the osteoblast-inactivating factors often varied among patients, indicating multiple mechanisms by which myeloma cells suppress osteoblastogenesis.
Recently, Pennisi et al
demonstrated that cell-surface “coupling” factors ephrinB2 and EphB4, which mediate communication between osteoblasts and osteoclasts by bidirectional signaling (Zhao et al, 2006
), are underexpressed in MSCs from patients with myeloma and that myeloma cells induce downregulation of these genes in healthy MSCs (Pennisi et al, 2009c
). Osteoclast precursors mainly express ephrinB2, whereas osteoblasts and their precursors, MSCs, express ephrinB2 and EphB4. Forward signaling in MSCs promotes their osteogenic differentiation, and reverse signaling in osteoclast precursors inhibits their differentiation into multinucleated bone-resorbing osteoclasts (Zhao et al, 2006
; Pennisi et al, 2009c
). Activating ephrinB2–EphB4 bidirectional signaling by using chimeric proteins ephrinB2-Fc and EphB4-Fc in the SCID-hu model for MM resulted in increased osteoblast activity and bone mass of the myelomatous bone (Pennisi et al, 2009c
). Inhibition of osteoclastogenesis, angiogenesis, and myeloma growth also were associated with treating mice with clustered EphB4-Fc (which stimulates reverse signaling) but not with clustered ephrinB2-Fc (which stimulates forward signaling). These studies indicate that cell-surface factors for coupling bone remodeling, such as ephrinB2 and particularly EphB4, are potential therapeutic targets for MM bone disease ().