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  • IL IL is another potential inhibitor of OBL

    2019-05-15

    IL-7: IL-7 is another potential inhibitor of OBL differentiation in MM that induces RANKL production by T lymphocytes [113] and mediates MM-induced OBL inhibition by down-regulating RUNX2 transcriptional activity [93]. IL-7 levels are increased in the marrow of MM patients and that IL-7 inhibited both early and late human osteoblast precursor differentiation in a dose-dependent manner, affecting the differentiation of early and late osteoblast precursors by targeting Runx2 activity, though it did not suppress Runx2 activity [114]. IL-7 can also induce GFI1, a transcriptional repressor of the Runx2 gene, and enhance the effects of suboptimal TNF-α on osteoblast suppression, resulting in further suppression of osteoblast differentiation [115]. GFI1: D\'Souza and colleagues recently reported that myeloma ABT737 manufacturer and primary marrow stromal cells from myeloma patients have elevated levels of Gf1 and that myeloma cells induce expression of GFI1 in marrow stromal cells. In addition, they demonstrate that GFI1 is a potent suppressor of osteoblast differentiation [116]. In preliminary studies Galson and colleagues have shown that GFI1 directly interacts with the RUNX2 promoter to block RUNX2 expression, that there are multiple GFI1 sites within the Runx2 promoter, and that mutation of the key GFI1 binding site prevents TNF-α repression of Runx2. GFI1 can also recruit histone deacetylases and other modifying enzymes to the RUNX2 promoter, possibly contributing to the long-term suppression of OBL activity present in MM patients [117]. Adiponectin: Adiponectin is an adipocyte-derived factor that can protect osteoblast differentiation in MM and increase myeloma cell apopotosis [118]. Adiponectin expression is decreased in both murine and human bone marrows permissive for myeloma growth and increasing adiponectin expression with the apolipoprotein peptide mimetic L-4F both reduces tumor burden and MMBD in murine models and, in the absence of myeloma cells, induces an increase in osteoblasts and bone formation without altering osteoclasts. Thus, induction of adiponectin expression is a potential therapeutic target for the osteoblast suppression of MMBD.
    Treatment of myeloma bone disease Bisphosphonates remain the standard of care for MM-related bone disease at this time. Bisphosphonates are potent inhibitors of OCL activity, and intravenous bisphosphonates given every 3–4 weeks are the current treatment of choice for the prevention of skeletal-related events. Bisphosphonate therapy slows progression of lytic lesions, prevents development of new pathologic fractures, and improves bone pain through inhibition of osteoclast activity. Oral clodronate treatment has been shown to reduce the development of osteolytic lesions, fractures, hypercalcemia, and bone pain in MM [119]. The Medical Research Council (MRC) IX trial demonstrated that iv zoledronic acid reduced the incidence of skeletal related events (SREs), (hypercalcemia, new bone lesions, and fractures) as compared with oral clodronate in patients with newly diagnosed MM [120]. In addition, patients treated with zoledronic acid had improved disease response rates and overall survival after a median follow-up of 3.7 years, compared with patients treated with clodronate. This suggests that bisphosphonates have a direct anti-myeloma effect, a hypothesis supported by in vitro data [121,122]. Intravenous pamidronate, 90mg monthly, or zoledronic acid, 4mg monthly, are the standard bisphosphonate therapies in myeloma. In the original randomized trial evaluating intravenous pamidronate therapy in myeloma, a significant reduction in the number of skeletal events per patient year was found when compared to placebo (1.3 versus 2.2) when patients were treated for 21 months [9]. When compared with pamidronate in phase III trials, zoledronic acid was found to be as effective as pamidronate in decreasing the number of skeletal complications and the need for radiation therapy [123]. The major benefit of zoledronic acid over pamidronate is that it can be given over a shorter period of time (15min. versus 2h).