Osteoclasts as effector cells in skeletal malignanciesSkeletal complications represent frequent and significant events in patients with multiple myeloma, and include osteolytic lesions, pathologic fractures, neurologic symptoms (pain, paralysis), and profound hypercalcemia. 1,2 At the cellular level, these complications are due to an excessive growth of malignant myeloma cells within the bone marrow microenvironment and their interactions with osteoblastic and osteoclastic lineage cells. 1,3,4 A consistent histologic finding in myeloma bone disease is enhanced and uncontrolled osteoclastic bone resorption adjacent to areas of plasma cell infiltrates. 2 Moreover, antiresorptive drugs that inhibit osteoclastic functions such as bisphosphonates are successfully used in patients with myeloma bone disease, indicating that osteoclasts are essential mediators in the pathogenesis of myeloma bone disease. 5 In the past 5 years, an essential cytokine system for osteoclast biology has been characterized. 6,7 This system consists of a ligand, receptor activator of NF-B ligand (RANKL), 8,9 a cellular receptor, RANK, 8,10 and a soluble decoy receptor, osteoprotegerin (OPG). 11 While RANKL stimulates several aspects of osteoclast function, thus enhancing bone resorption, OPG blocks RANKL, and prevents bone resorption. 9,12 Abnormalities of this system have been implicated in the pathogenesis of various skeletal diseases characterized by enhanced osteoclastic activity and increased bone resorption, including osteolytic metastasis and tumor-associated hypercalcemia. 13 RANKL and OPG in bone cell biologyOsteoclasts are derived from macrophagic/monocytic lineage cells and represent differentiated, multinucleated cells specialized in resorbing bone. 6,7 Recently, the essential cytokines of osteoclast biology have been identified and extensively characterized. Osteoclastic lineage cells express RANK, a member of the tumor necrosis factor receptor superfamily. 8,10 Following activation of RANK by its ligand, RANKL, differentiation, proliferation, and survival of preosteoclast is enhanced, osteoclastic fusion and activation is promoted, and osteoclastic apoptosis is suppressed, resulting in a marked increase of the number and activity of osteoclasts. 9,12 RANKL is mainly produced by osteoblastic lineage cells, 14 immune cells, 8,15 and some cancer cells. 16,17 This provides the cellular and molecular basis for osteoblast-osteoclast cross-talks, which are crucial for an orderly sequence of bone resorption and formation during bone remodeling. 14 However, RANKL production by immune and cancer cells also forms the basis of skeletal complications of inflammatory and malignant diseases, because activated T cells and cancer cells are able to directly activate RANK on osteoclasts by virtue of expressing RANKL. 4,7 The potent stimulatory effects of RANKL on RANK are counteracted by a safeguard mechanism. Many cell types-in the bone marrow microenvironment, mainly osteoblastic lineage cells-secrete OPG, which acts as a decoy receptor and bloc...

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These data show that treatment with bortezomib leads to enhanced markers of osteoblast activity in patients with myeloma. The comparison with the control group suggests that the effect on osteoblasts is unique to the proteasome inhibitor.

The proteasome is a proteolytic complex for intracellular degradation of ubiquitinated proteins which are involved in cellcycle regulation and apoptosis. A constitutively increased proteasome activity has been found in myeloma cells. We studied circulating proteasome levels and their prognostic significance in sera of 50 control subjects, 20 persons with monoclonal gammopathies of undetermined significance (MGUS), and 141 previously untreated patients with multiple myeloma (MM) by an anti-20S proteasome enzymelinked immunoabsorbent assay (ELISA). Serum proteasome concentrations were significantly elevated in MM compared with controls (P < .001), in MM versus MGUS (P ‫؍‬ .03), and in active (n ‫؍‬ 101) versus smoldering (n ‫؍‬ 40) MM (P < .001). In patients with active MM, there was a significant (P < .001) decrease from pretreatment to post-treatment proteasome concentrations in responders to chemotherapy, but not in nonresponders. Circulating proteasome levels were identified as a prognostic factor for overall survival in the univariate (P < .001 log-rank test) and in the multivariate (hazard ratio, 4.38) survival analysis in patients with active MM. We demonstrate for the first time that increased serum proteasome concentrations correlate with advanced disease and are an independent prognostic factor in MM. (Blood. 2007;109:2100-2105)

The importance of neoangiogenesis for the progressive growth and viability of solid tumors is well established. Recently, there has been growing evidence that angiogenesis might also be important in hematological malignancies, but only few data are available. In this report, we have studied the impact of bone marrow microvessel density and survival in patients with multiple myeloma (MM). Immunohistochemical CD34 stained paraffin-embedded bone marrow biopsies of 44 patients with newly diagnosed MM were studied. Microvessels were counted in 400 x magnification and the mean number of vessels per area in each sample was noted as the microvessel density (MVD). The median MVD was 48 vessels/mm2, the range was 0-125 vessels/mm2. Using a cut-off value of the median MVD in the Kaplan-Meier analysis, the median survival was 22.2 months in the group with the higher MVD and was not reached in the group with the lower MVD (P< 0.01). In a multivariate Cox regression analysis, using previously identified prognostic factors beta2-microglobulin, C-reactive protein (CRP), and age, MVD remained significant as a prognostic factor (P< 0.03).

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Based on these findings, we provide evidence that HDAC inhibitors have antiproliferative effects in MCL and may represent a promising therapeutic approach.

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