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  • The canonical or catenin dependent Wnt signaling pathway is


    The canonical, or β-catenin dependent, Wnt signaling pathway is critical for the regulation of osteoblast proliferation and survival [95]. Soluble inhibitors of the canonical Wnt pathway such as Dickkopf (DKK1), produced by OBL, and sclerostin, from osteocytes, play important roles in the regulation of bone mass in MM. Additionally, secreted Wnt inhibitors such as the secreted frizzled related proteins (sFRP) [96] can inhibit the canonical as well as the non-canonical Wnt pathways by binding to frizzled. DKK1: DKK1 is a major inhibitor of OBL differentiation in myeloma by sequestering low-density lipoprotein receptor-related protein (LRP) 5/6 from binding WNT, ultimately downregulating RUNX2 activity [97–99]. Tian and coworkers reported that primary CD138+ cells from myeloma patients but not MGUS patients produce DKK1, and demonstrated that levels of DKK1 mRNA correlate with the number of focal bone lesions in patients with MM [100]. Others have similarly reported that serum DKK1 levels correlate with the extent of bone disease in MM patients [101], however this finding is controversial as DKK1 expression is lost as MM bone disease progresses [100]. Preclinical studies with aa-dutp that block DKK1 (BHQ880) have shown that these compounds enhance bone formation and block tumor growth in murine models of myeloma bone disease [102]. However, MM patients with advanced disease do not express DKK1, suggesting that Wnt inhibitors may mediate bone destruction only in the early phases of disease [100]. In addition to inhibiting osteoblastogenesis, elevated DKK1 levels can also enhance osteoclastogenesis. Wnt signaling in OBLs increases expression of OPG [103] and down-regulates the expression of RANKL [104], suggesting a possible mechanism by which inhibition of Wnt signaling in OBL would indirectly increase osteoclastogenesis. Taken together, these studies indicate that DKK1 is a key regulator of bone remodeling in both physiological and pathological conditions and that blocking this factor may contribute to both stimulation of osteoclastogenesis and inhibition of OBL in myelomatous bones. Sclerostin: Sclerostin is an inhibitor of the canonical downstream Wnt signaling pathway that is produced by osteocytes to inhibit osteoblast differentiation. Several studies have recently demonstrated that myeloma cells may produce sclerostin or induce sclerostin expression in myeloma patients [105,106], and sclerostin levels correlate with bone destruction in myeloma [107]. In addition, osteocyte apopotosis has been reported in myeloma, and apoptotic osteocytes may release both RANKL and sclerostin [108]. HGF: HGF is a negative regulator of BMP-induced osteoblast differentiation [59]. A myeloma cell line, that produces large amounts of HGF, JJN3, causes 99% loss of osteoblast perimeter when injected into irradiated SCID mice. Myeloma patients with elevated HGF levels in their sera have lower bone specific alkaline phosphatase activity (a marker of osteoblast function) when compared to patients without HGF elevations, and HGF has been shown to inhibit human osteoblast formation [109]. TGFβ: TGFβ is deposited into bone matrix in a latent form by osteocytes and osteoblasts and released in an active form by the enhanced OCL activity in MMBD. TGFβ inhibits osteoblast differentiation in MMBD, and blockade of TGFβ signaling via the TGFβ type I receptor by an inhibitor of the receptor\'s kinase function, Ki26894, restores osteoblast differentiation suppressed by either TGFβ, myeloma cell line conditioned media, or bone marrow plasma from MM patients [110]. Oral administration of Ki26894 to a SCID-rab model of MMBD injected with INA-6 myeloma cells demonstrated that in vivo targeting of TGFβ signaling decreased MM cell growth in the bone, protected the bone from destruction, and preserved osteoblast differentiation. TGFβ family members, including BMPs and activin, also modulate OBL differentiation. BMP2 stimulates OBL differentiation via SMAD signaling activation [111], while activin A-mediated upregulation of SMAD2 pathways results aa-dutp in both stimulation of OCL differentiation and function described previously in this review and impairment of osteoblastogenesis [74]. Additionally, activin A levels correlate with advanced ISS stage, bone disease, and decreased survival in patients at diagnosis and relapse [112].