Bone Marrow Microenvironmental Overexpression of DKK1, HGF, Frizzled-Related Protein B, and Syndecan-1 Are Associated with the Degree of Osteolytic Bone Disease in Multiple Myeloma Patients

Gene expression analysis of 8 different genes in homogenized bone marrow trephine biopsies from 47 newly diagnosed, untreated MM patients with different degrees of osteolytic bone disease (OBD) and 19 MGUS patients were analysed by quantitative PCR technique. The analysed genes represent both genes suspected to be involved in osteoblast inhibition (DKK1, HGF, Frizzled-related protein B, Syndecan-1) and osteoclast activation (RANKL, MIP-1α), and genes involved in the regulation of these genes (OPG, RANK). The expression levels of these 8 genes in the biopsies represent the net gene expression in bone marrow microenvironment including MM cells, hematopoietic cells, stromal cells, osteoblasts, and osteoclasts. OBD was graded into no, limited, or advanced by standard radiography. The expression level of DKK1 increased significantly with more advanced OBD (p=0.005), whereas the expression level between the MGUS group and the MM group with no/limited OBD was not significantly different (p= 0.097). Syndecan-1 was expressed in all BM-samples from MGUS and MM patients. Syndecan-1 expression was significantly increased with more advanced OBD and was significantly different between the three bone morbidity groups. The expression of Syndecan-1 was, furthermore, closely correlated to PC numbers in the BM samples (p< 0.0001). HGF and FRPB expressions in the MM group with no/low OBD and MM group with advanced OBD was not statistically different but HGF and FRPB expression was significantly increased in the MM groups compared with the MGUS group. OPG expression showed a trend towards being decreased with more advanced OBD. There were no correlation between the degree of OBD and the expression levels of MIP1a, RANKL, and RANK. Thus, in this BM microenvironment expression profile study we found that inhibitors of the Wnt signalling pathways, DKK1 and Frizzled-related protein B, and the inhibition of osteoblastogenesis by HGF, seem to play an important role in the pathogenesis of OBD in MM. In the contrary, we did not find a significant correlation between up-regulation of the osteoclast activating cytokines, RANKL and MIP1α, with more advanced OBD, and we did not find a correlation between the expression level of the RANKL receptor, RANK, and the degree of OBD.