A new xenograft model of myeloma bone disease demonstrating the efficacy of human mesenchymal stem cells expressing osteoprotegerin by lentiviral gene transfer

Abstract

We describe a new model of myeloma bone disease in which b 2 m NOD/SCID mice injected with KMS-12-BM cells develop medullary disease after tail vein administration. Micro-computed tomography analysis demonstrated significant bone loss in the tibiae and vertebrae of diseased animals compared to controls, with loss of cortical bone (Po0.01), as well as trabecular bone volume, thickness and number (Po0.05 for all). Bone marrow of diseased animals demonstrated an increase in osteoclasts (Po0.01) and reduction in osteoblasts (Po0.01) compared to control animals. Both bone loss and osteoclast increase correlated with the degree of disease involvement. Mesenchymal stem cells (MSCs) were lentivirally transduced to express human osteoprotegerin (hOPG). Systemic administration of OPG expressing MSC reduced osteoclast activation (Po0.01) and trabecular bone loss in the vertebrae (Po0.05) and tibiae of diseased animals, to levels comparable to non-diseased controls. Because of its predominantly medullary involvement and quantifiable parameters of bone disease, the KMS-12-BM xenogeneic model provides unique opportunities to test therapies targeted at the bone marrow microenvironment.

Therapeutic potential of genetically modified mesenchymal stem cells

“…The potential of MSC, modified to express osteogenic factors, in bone regeneration can be adapted to treat bone damage in cancer patients with osteolytic lesions. Rabin et al 46 used MSC, transduced by a lentivirus vector to express human OPG (osteoprotegerin), for the treatment of osteolysis in KMS-12-BM xenogenic model of myeloma bone disease. The primary mechanism for bone destruction in bone metastasis is due to osteoclastic bone resorption.…”

“…Notably, systemic expression of OPG, using MSC, has been shown to significantly reduce osteoclast activity and trabecular bone loss in the vertebrae and tibiae of diseased animals. 46 Similarly, bone targeted expression of factors preventing osteoblast production such as noggin can be adapted to minimize osteoblast bone pathology in prostate cancer.…”

Spotlight review series on multiple myeloma

“…1,2 These advances, although helped by a few serendipitous observations, are associated with a major improvement in our understanding of myeloma cytogenetics and biology, and a greater realization of the role played by the bone marrow microenvironment in disease pathogenesis and progression. [3][4][5][6] Myeloma evolves from an asymptomatic premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS), which is prevalent in over 3% of the population above the age of 50 years. 7 MGUS seems to originate as an aberrant response to antigenic stimulation mediated by aberrant Toll-like receptor (TLR) expression.…”

Mouse models and the RANKL/OPG axis in myeloma bone disease

“…Skeletal lesions cause pain, present a risk of pathological fracture and can lead to spinal cord compression. In this issue of Leukemia, Rabin et al, 1 describe an animal model of myeloma bone disease that enhances our understanding of the mechanisms behind bone destruction and provides further evidence of the potential therapeutic use of osteoprotegerin (OPG) in preventing this complication. Studies using magnetic resonance imaging have identified three patterns of bone marrow involvement: focal accumulation of cells (multiple plasmacytomas), diffuse marrow infiltration or a mixed pattern of focal and diffuse disease.…”

“…The KMS-12-BM model exhibits minimal extramedullary spread (liver) and reliably produces lytic bone lesions. 1 The main problem in relation to all these models is that human myeloma cell lines are growing in a murine environment. It is well known that many human plasma membrane receptors do not recognize murine growth factors and vice versa.…”