Rebecca Silbermann

Bone marrow monocyte-/macrophage-derived activin A mediates the osteoclastogenic effect of IL-3 in multiple myeloma.

Bone marrow monocyte-/macrophage-derived activin A mediates the osteoclastogenic effect of IL-3 in multiple myeloma

Mechanisms of multiple myeloma bone disease

Multiple myeloma is the second most common hematological malignancy and the most frequent cancer to involve the skeleton. Multiple myeloma bone disease (MMBD) is characterized by abnormal bone remodeling with dysfunction of both bone resorption and bone formation, and thus can be used as a paradigm for other inflammatory bone diseases, and the regulation of osteoclasts and osteoblasts in malignancy. Studies of MMBD have identified novel regulators that increase osteoclastogenesis and osteoclast function, repress osteoblast differentiation, increase angiogenesis, or permanently alter stromal cells. This review will discuss the current understanding of mechanisms of osteoclast and osteoblast regulation in MMBD, and therapeutic approaches currently in use and under development that target mediators of bone destruction and blockade of bone formation for myeloma patients, including new anabolic therapies.

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.

Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo

We reported that p62 (sequestosome 1) serves as a signaling hub in bone marrow stromal cells (BMSCs) for the formation of signaling complexes, including NFκB, p38MAPK and JNK, that are involved in the increased osteoclastogenesis and multiple myeloma (MM) cell growth induced by BMSCs that are key contributors to multiple myeloma bone disease (MMBD), and demonstrated that the ZZ domain of p62 (p62-ZZ) is required for BMSC enhancement of MMBD. We recently identified a novel p62-ZZ inhibitor, XRK3F2, which inhibits MM cell growth and BMSC growth enhancement of human MM cells. In the current study, we evaluate the relative specificity of XRK3F2 for p62-ZZ, characterize XRK3F2’s capacity to inhibit growth of primary MM cells and human MM cell lines, and test the in vivo effects of XRK3F2 in the immunocompetent 5TGM1 MM model. We found that XRK3F2 induces dramatic cortical bone formation that is restricted to MM containing bones and blocked the effects and upregulation of tumor necrosis factor alpha (TNFα), an osteoblast (OB) differentiation inhibitor that is increased in the MM bone marrow microenvironment and utilizes signaling complexes formed on p62-ZZ, in BMSC. Interestingly, XRK3F2 had no effect on non-MM bearing bone. These results demonstrate that targeting p62 in MM models has profound effects on MMBD.

Mechanisms of osteolytic and osteoblastic skeletal lesions

The bone is a frequent site for tumor metastasis, and cancer in the bone results in marked disturbances of bone remodeling that can be lytic, blastic or a combination of the two. Patients with advanced malignancies that have metastasized to the bone frequently suffer from debilitating skeletal-related events, including pathologic fractures, spinal cord compression syndromes, disorders of calcium and phosphate homeostasis and severe cancer-related pain. This review will discuss recent studies on the mechanisms responsible for osteolytic and osteoblastic metastasis and how their identification has resulted in the development of new agents for patients with metastatic bone disease.

Bone effects of cancer therapies: pros and cons.

Purpose of reviewAgents used for systemic chemotherapy can alter normal bone homeostasis through mechanisms that affect both osteoblast and osteoclast function. The identification of those agents that influence maintenance of the bone-remodeling compartment is an important component of the drug development and testing process. This brief review focuses on preclinical and clinical data illustrating the effect of several classes of chemotherapeutic agents on skeletal development and bone remodeling. Recent findingsNew preclinical data demonstrate that several classes of chemotherapeutic agents, including histone deacetylase inhibitors and proteasome inhibitors, alter osteoblast and osteoclast function. Preclinical data on retinoic acid analogues demonstrate that these agents inhibit osteoclastogenesis. In addition, a dose-dependent effect of methotrexate treatment on growth plate thickness and primary spongiosa height in rats has been demonstrated. Two recently published analyses of clinical data from trials of bortezomib in myeloma patients found increased biochemical markers of bone formation and evidence of increased bone deposition after bortezomib treatment. SummarySeveral classes of chemotherapeutic agents alter bone metabolism and negatively impact bone homeostasis. Bone mineral density (BMD) monitoring guidelines for patients receiving systemic chemotherapy are not established. Limited guidelines exist for BMD monitoring in patients receiving long-term hormonal modulation; however, the negative effect of other chemotherapeutic agents on the skeleton is underappreciated.

Preclinical animal models of multiple myeloma

Multiple myeloma is an incurable plasma-cell malignancy characterized by osteolytic bone disease and immunosuppression. Murine models of multiple myeloma and myeloma bone disease are critical tools for an improved understanding of the pathogenesis of the disease and the development of novel therapeutic strategies. This review will cover commonly used immunocompetent and xenograft models of myeloma, describing the advantages and disadvantages of each model system. In addition, this review provides detailed protocols for establishing systemic and local models of myeloma using both murine and human myeloma cell lines.

Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis

BackgroundIn spite of major advances in treatment, multiple myeloma (MM) is currently an incurable malignancy due to the emergence of drug-resistant clones. We previously showed that MM cells upregulate the transcriptional repressor, growth factor independence 1 (Gfi1), in bone marrow stromal cells (BMSCs) that induces prolonged inhibition of osteoblast differentiation. However, the role of Gfi1 in MM cells is unknown.MethodsHuman primary CD138+ and BMSC were purified from normal donors and MM patients’ bone marrow aspirates. Gfi1 knockdown and overexpressing cells were generated by lentiviral-mediated shRNA. Proliferation/apoptosis studies were done by flow cytometry, and protein levels were determined by Western blot and/or immunohistochemistry. An experimental MM mouse model was generated to investigate the effects of MM cells overexpressing Gfi1 on tumor burden and osteolysis in vivo.ResultsWe found that Gfi1 expression is increased in patient’s MM cells and MM cell lines and was further increased by co-culture with BMSC, IL-6, and sphingosine-1-phosphate. Modulation of Gfi1 in MM cells had major effects on their survival and growth. Knockdown of Gfi1 induced apoptosis in p53-wt, p53-mutant, and p53-deficient MM cells, while Gfi1 overexpression enhanced MM cell growth and protected MM cells from bortezomib-induced cell death. Gfi1 enhanced cell survival of p53-wt MM cells by binding to p53, thereby blocking binding to the promoters of the pro-apoptotic BAX and NOXA genes. Further, Gfi1-p53 binding could be blocked by HDAC inhibitors. Importantly, inoculation of MM cells overexpressing Gfi1 in mice induced increased bone destruction, increased osteoclast number and size, and enhanced tumor growth.ConclusionsThese results support that Gfi1 plays a key role in MM tumor growth, survival, and bone destruction and contributes to bortezomib resistance, suggesting that Gfi1 may be a novel therapeutic target for MM.

The Role of the Immune System in the Effects of Cancer on Bone

Abstract In this chapter, the contributions of cells in the immune system (monocyte-macrophages, myeloid derived suppressor cells, mesenchymal stromal cells, T cell subsets, NK cells, dendritic cells, and B cells) to bone metastasis, and multiple myeloma bone disease will be reviewed. In addition, the effects of tumor-derived products, such as lactic acid, that is also produced by bone cells, on the suppression of antitumor responses that are required for tumor growth in bone, will be discussed. All of these components of the immune system are major contributors to the growth and bone altering effects of tumor cells in bone.

Mechanisms of Bone Destruction in Myeloma

Multiple myeloma (MM) is a plasma cell malignancy characterized by monoclonal paraprotein production. It is the second most common hematologic malignancy and has the highest incidence of bone involvement amongst malignant diseases. Up to 90% of patients with MM have evidence of osteolysis in the form of generalized osteopenia or discrete lytic lesions. Skeletal lesions in MM are distinct from bone involvement in other malignancies and are characterized by generalized increased osteoclast activity and suppressed osteoblast function with decreased new bone formation. This chapter will review the pathophysiology of myeloma bone disease and discuss current treatment strategies and novel targets for management of myeloma bone disease.