Osteoclasts Pump Iron

SummaryOsteoclasts are the primary cells that resorb bone; they require high energy levels to degrade bone matrix, releasing minerals to maintain calcium homeostasis. Recent work on osteoclast differentiation and activity highlights an important role for mitochondrial biogenesis and explores the role of iron transferrin in generating a positive osteoclastogenic feedback loop

Myeloma bone disease: Pathophysiology and management.

Multiple myeloma bone disease is marked by severe dysfunction of both bone formation and resorption and serves as a model for understanding the regulation of osteoblasts (OBL) and osteoclasts (OCL) in cancer. Myeloma bone lesions are purely osteolytic and are associated with severe and debilitating bone pain, pathologic fractures, hypercalcemia, and spinal cord compression, as well as increased mortality. Interactions within the bone marrow microenvironment in myeloma are responsible for the abnormal bone remodeling in myeloma bone disease. Myeloma cells drive bone destruction that increases tumor growth, directly stimulates the OCL formation, and induces cells in the marrow microenvironment to produce factors that drive OCL formation and suppress OBL formation. Factors produced by marrow stromal cells and OCL promote tumor growth through direct action on myeloma cells and by increasing angiogenesis. Current therapies targeting MMBD focus on preventing osteoclastic bone destruction; however regulators of OBL inhibition in MMBD have also been identified, and targeted agents with a potential anabolic effect in MMBD are under investigation. This review will discuss the mechanisms responsible for MMBD and therapeutic approaches currently in use and in development for the management of MMBD

Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts

Despite recent progress in its treatment, Multiple Myeloma (MM) remains incurable and its associated bone disease persists even after complete remission. Thus, identification of new therapeutic agents that simultaneously suppress MM growth and protect bone is an unmet need. Herein, we examined the effects of Aplidin, a novel anti-cancer marine-derived compound, on MM and bone cells. In vitro, Aplidin potently inhibited MM cell growth and induced apoptosis, effects that were enhanced by dexamethasone (Dex) and bortezomib (Btz). Aplidin modestly reduced osteocyte/osteoblast viability and decreased osteoblast mineralization, effects that were enhanced by Dex and partially prevented by Btz. Further, Aplidin markedly decreased osteoclast precursor numbers and differentiation, and reduced mature osteoclast number and resorption activity. Moreover, Aplidin reduced Dex-induced osteoclast differentiation and further decreased osteoclast number when combined with Btz. Lastly, Aplidin alone, or suboptimal doses of Aplidin combined with Dex or Btz, decreased tumor growth and bone resorption in ex vivo bone organ cultures that reproduce the 3D-organization and the cellular diversity of the MM/bone marrow niche. These results demonstrate that Aplidin has potent anti-myeloma and anti-resorptive properties, and enhances proteasome inhibitors blockade of MM growth and bone destruction

Role of osteocytes in multiple myeloma bone disease

PURPOSE OF REVIEW: Despite the increased knowledge of osteocyte biology, the contribution of this most abundant bone cell to the development and progression of multiple myeloma in bone is practically unexplored. RECENT FINDINGS: Multiple myeloma bone disease is characterized by exacerbated bone resorption and the presence of osteolytic lesions that do not heal because of a concomitant reduction in bone formation. Osteocytes produce molecules that regulate both bone formation and resorption. Recent findings suggest that the life span of osteocytes is compromised in multiple myeloma patients with bone lesions. In addition, multiple myeloma cells affect the transcriptional profile of osteocytes by upregulating the production of pro-osteoclastogenic cytokines, stimulating osteoclast formation and activity. Further, patients with active multiple myeloma have elevated circulating levels of sclerostin, a potent inhibitor of bone formation which is specifically expressed by osteocytes in bone. SUMMARY: Understanding the contribution of osteocytes to the mechanisms underlying the skeletal consequences of multiple myeloma bone disease has the potential to provide important new therapeutic strategies that specifically target multiple myeloma-osteocyte interactions

SuperB: a linear high-luminosity B Factory

This paper is based on the outcome of the activity that has taken place during the recent workshop on "SuperB in Italy" held in Frascati on November 11-12, 2005. The workshop was opened by a theoretical introduction of Marco Ciuchini and was structured in two working groups. One focused on the machine and the other on the detector and experimental issues. The present status on CP is mainly based on the results achieved by BaBar and Belle. Estabilishment of the indirect CP violation in B sector in 2001 and of the direct CP violation in 2004 thanks to the success of PEP-II and KEKB e+e- asymmetric B Factories operating at the center of mass energy corresponding to the mass of the Y(4s). With the two B Factories taking data, the Unitarity Triangle is now beginning to be overconstrained by improving the measurements of the sides and now also of the angles alpha, and gamma. We are also in presence of the very intriguing results about the measurements of sin(2 beta) in the time dependent analysis of decay channels via penguin loops, where b --> s sbar s and b --> s dbar d. Tau physics, in particular LFV search, as well as charm and ISR physics are important parts of the scientific program of a SuperB Factory. The physics case together with possible scenarios for the high luminosity SuperB Factory based on the concepts of the Linear Collider and the related experimental issues are discussed.Comment: 22 pages, 22 figures, INFN Roadmap Repor

Therapeutic targets in myeloma bone disease

Multiple myeloma (MM) is the second‐most‐common hematologic malignancy and is characterized by a clonal proliferation of neoplastic plasma cells within the bone marrow. MM is the most frequent cancer involving the skeleton, causing osteolytic lesions, bone pain, and pathological fractures that dramatically decrease MM patients’ quality of life and survival. MM bone disease (MBD) results from uncoupling of bone remodelling in which excessive bone resorption is not compensated by new bone formation, due to a persistent suppression of osteoblast activity. Current management of MBD includes anti‐resorptive agents i.e. bisphosphonates and denosumab that are only partially effective due to their inability to repair the existing lesions. Thus, research into agents that prevent bone destruction and more importantly repair existing lesions by inducing new bone formation, is of the utmost importance. This review discusses the mechanisms regulating the uncoupled bone remodelling in MM, and summarizes current advances in the treatment of MBD