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  • RANK RANKL The RANK RANKL

    2019-05-09

    RANK/RANKL: The RANK/RANKL signaling pathway is a critical component of both normal and malignant bone remodeling. RANK is a transmembrane signaling receptor and a member of the tumor necrosis receptor (TNF) superfamily that is found on the surface of OCL precursors [43,44]. RANK ligand (RANKL) is expressed as a membrane-bound protein on marrow stromal focal adhesion kinase and OBL that is secreted by activated lymphocytes. RANKL expression is induced by cytokines that stimulate bone resorption [45] such as PTH, 1,25-OH Vitamin D3, prostaglandins [46,47], and myeloma cells themselves both produce and induce production of RANKL by marrow stromal cells via adhesive interactions described above, as well as by soluble factors produced by myeloma cells such as Dickkopf1 (DKK1) [48] and TNF-α [49]. In addition, RANKL further increases OCL formation and survival by binding to RANK [50]. OPG, the soluble décor receptor for RANKL, is critical for the regulation of lytic activity in both normal and myelomatous bone [51]. OPG is produced by OBL in the marrow and blocks the interactions of RANKL with RANK, limiting osteoclastogenesis. The RANKL/OPG ratio in the marrow microenvironment in MM is skewed in favor of RANKL [30], and the ratio of RANKL to OPG in the sera of myeloma patients impacts prognosis. Patients with high RANKL:OPG ratios have inferior survival as compared to patients with normal or intermediate RANKL:OPG ratios [52]. Furthermore, preclinical models of myeloma demonstrated that inhibition of RANKL with OPG prevented bone destruction in animal MM models [52–54]. The clinical impact of denosumab, a human monoclonal antibody to RANKL, on bone metastases in patients with osteoporosis, breast cancer, prostate cancer, and treatment-induced bone disease due to prostate cancer has recently been evaluated, and is discussed later in this review. TNF-α: TNF-α is elevated in myeloma patients [55] and has multiple functions in MMBD. Myeloma cells induce high levels of TNF-α in the marrow microenvironment [56];,however it has been difficult to clearly demonstrate that myeloma cells themselves produce significant quantities of this cytokine [57]. Myeloma cells and TNF-α increase the transcription factor XBP1 in marrow stromal cells, which contributes to the increased production of VCAM1, RANKL, and IL-6 and enhances stromal cell support of myeloma cell growth and osteoclast formation. In addition, TNF-α is itself a potent inducer of osteoclast formation, and can directly increase osteoclast formation and enhance the effects of RANKL[58]. TNF-α also can block osteoblast differentiation from marrow stromal cells by decreasing expression of critical osteoblast transcription factors such as Runx2, TAZ, and Osx, induce apoptosis of mature osteoblasts, and increase support of myeloma cells by induction of IL-6 [23,59]. MIP-1α: MIP-1α (CCL3) is a potent chemokine produced by MM cells in 70% of patients that induces OCL formation and has recently also been found to inhibit osteoblast function [60]. MIP-1α acts as a chemotactic factor for OCL precursors and can induce differentiation of OCL progenitors, contributing to OCL formation [61–63] independent of RANKL. In addition, MIP-1α potentiates both RANKL and IL-6 stimulated OCL formation [64] and plays a role in homing of MM cells to the bone marrow by enhancing myeloma cell adhesion to marrow stromal cells by increasing expression of β1 integrins on MM cells[65]. This enhances marrow stromal cell production of OAFs and the angiogenic factor VEGF. Elevated MIP-1α gene expression and secretion by myeloma cells is highly correlated with bone destruction and decreased patient survival in MM [66]. Translocation 4:14 in MM cells, associated with poor patient prognosis, has been shown to induce constitutive expression of the fibroblast growth factor receptor 3 (FGFR3), resulting in high focal adhesion kinase levels of MIP-1α [67]. In vivo murine models of MM have demonstrated that MIP-1α can induce OCL formation and bone destruction. Blocking MIP-1α expression in MM cells injected into SCID mice or treating the animals with a neutralizing antibody to MIP-1α results in decreased tumor burden and bone destruction [62,68].