ABSTRACT
Multiple myeloma is a B-cell malignancy characterized by the accumulation of plasma cells in the bone marrow and the development of osteolytic bone disease. The present study demonstrates that myeloma cells express the critical osteoclastogenic factor RANKL (the ligand for receptor activator of NF-kappa B). Injection of 5T2MM myeloma cells into C57BL/KaLwRij mice resulted in the development of bone disease characterized by a significant decrease in cancellous bone volume in the tibial and femoral metaphyses, an increase in osteoclast formation, and radiologic evidence of osteolytic bone lesions. Dual-energy x-ray absorptiometry demonstrated a decrease in bone mineral density (BMD) at each of these sites. Treatment of mice with established myeloma with recombinant osteoprotegerin (OPG) protein, the soluble decoy receptor for RANKL, prevented the development of lytic bone lesions. OPG treatment was associated with preservation of cancellous bone volume and inhibition of osteoclast formation. OPG also promoted an increase in femoral, tibial, and vertebral BMD. These data suggest that the RANKL/RANK/OPG system may play a critical role in the development of osteolytic bone disease in multiple myeloma and that targeting this system may have therapeutic potential.
Subject(s)
Glycoproteins/therapeutic use , Multiple Myeloma/complications , Osteolysis/prevention & control , Receptors, Cytoplasmic and Nuclear/therapeutic use , Animals , Bone Density , Bone and Bones/pathology , Carrier Proteins/analysis , Carrier Proteins/genetics , Flow Cytometry , Gene Expression , Glycoproteins/administration & dosage , Male , Membrane Glycoproteins/analysis , Membrane Glycoproteins/genetics , Mice , Mice, Inbred C57BL , Multiple Myeloma/chemistry , Multiple Myeloma/pathology , Neoplasm Transplantation , Osteolysis/etiology , Osteolysis/pathology , Osteoprotegerin , RANK Ligand , RNA, Messenger/analysis , Receptor Activator of Nuclear Factor-kappa B , Receptors, Cytoplasmic and Nuclear/administration & dosage , Receptors, Tumor Necrosis Factor , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Regulation of bone formation is important in the pathogenesis of many conditions such as osteoporosis, fracture healing, and loosening of orthopedic implants. We have recently identified a novel rat cDNA (best5) by differential display PCR that is regulated during osteoblast differentiation and bone formation in vitro and in vivo. Expression of best5 mRNA is induced in cultures of osteoblasts by both interferon-alpha (IFN-alpha) or IFN-gamma. Whereas IFN-alpha induced a rapid, transient induction of best5 expression peaking at 4-6 h poststimulation, IFN-gamma elicited a more prolonged induction of best5 expression, which remained elevated 48 h poststimulation. A polyclonal antibody generated to a peptide derived from the best5 coding region recognized a 27 kDa protein on Western blot analysis of osteoblast lysates. We localized BEST5 protein in osteoblast progenitor cells and mature osteoblasts in sections of rat tibiae and in sections of bones loaded in vivo to induce adaptive bone formation. Best5 may therefore be a fundamental intermediate in the response of osteoblasts to stimuli that modulate proliferation/differentiation, such as interferons or mechanical loading. These findings highlight the close interactions between the immune system and bone cells and may open new therapeutic avenues in modulating bone mass.