Enhanced production of osteopontin in multiple myeloma: clinical and pathogenic implications

Summary. In this study, we examined osteopontin (OPN) production in myeloma cells and plasma OPN levels in multiple myeloma (MM) patients. We assessed OPN production in bone marrow cells (BMCs) by immunocytochemistry and enzyme‐linked immunosorbent assay (ELISA). We also assessed OPN production in various B‐cell malignant cell lines, including three myeloma cell lines by reverse transcription polymerase chain reaction (RT‐PCR) and Western blotting. In addition, we measured plasma OPN concentrations by ELISA in 30 MM patients, 21 monoclonal gammopathy of undetermined significance (MGUS) patients and 30 healthy volunteers. As a result, in an immunocytochemical study, abundant OPN was detected in BMCs from overt MM patients, whereas no OPN was detected in BMCs from patients with other haematological diseases, including MGUS. Cultured BMCs from overt MM patients produced more OPN than those from patients with either smouldering MM or MGUS. Myeloma cell lines spontaneously produced OPN. Plasma OPN levels of MM patients were significantly higher than those of MGUS patients and healthy volunteers (P < 0·05). Moreover, they correlated with both progression and bone destruction of the disease (P < 0·05). These suggest that myeloma cells actively produce OPN, which possibly contributes to osteoclastic bone resorption in MM. Plasma OPN levels may be a useful biomarker for assessing bone destruction in MM and distinguishing MM from MGUS or smouldering MM.

[1]  Y. Saeki,et al.  Enhanced local production of osteopontin in rheumatoid joints. , 2002, The Journal of rheumatology.

[2]  M. Noda,et al.  Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Y. Saeki,et al.  Expression of osteopontin at sites of bone erosion in a murine experimental arthritis model of collagen-induced arthritis: possible involvement of osteopontin in bone destruction in arthritis. , 2002, Arthritis and rheumatism.

[4]  A. Chambers,et al.  Mapping of functional epitopes of osteopontin by monoclonal antibodies raised against defined internal sequences , 2002, Journal of cellular biochemistry.

[5]  I. Holen,et al.  Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. , 2001, Blood.

[6]  M. Noda,et al.  Parathyroid Hormone-induced Bone Resorption Does Not Occur in the Absence of Osteopontin* , 2001, The Journal of Biological Chemistry.

[7]  J. Kurebayashi,et al.  Expression and In Vitro Modification of Parathyroid Hormone-Related Protein (PTHrP) and PTH/PTHrP-Receptor in Human Myeloma Cells , 2001, Leukemia & lymphoma.

[8]  P. Petrow,et al.  Expression of osteopontin messenger RNA and protein in rheumatoid arthritis: effects of osteopontin on the release of collagenase 1 from articular chondrocytes and synovial fibroblasts. , 2000, Arthritis and rheumatism.

[9]  K. Tanaka,et al.  Antibodies to different peptides in osteopontin reveal complexities in the various secreted forms , 2000, Journal of cellular biochemistry.

[10]  R. Hynes,et al.  Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. , 2000, The Journal of clinical investigation.

[11]  R. Kyle,et al.  Monoclonal gammopathies of undetermined significance. , 2002, Reviews in clinical and experimental hematology.

[12]  M Noda,et al.  Osteopontin-deficient mice are resistant to ovariectomy-induced bone resorption. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[13]  S. Akira,et al.  Inducible expression of nuclear factor IL-6 increases endogenous gene expression of macrophage inflammatory protein-1 alpha, osteopontin and CD14 in a monocytic leukemia cell line. , 1998, International immunology.

[14]  Y. Matsuo,et al.  Establishment and characterization of human B cell precursor-leukemia cell lines. , 1998, Leukemia research.

[15]  G. Roodman.  Mechanisms of bone lesions in multiple myeloma and lymphoma , 1997, Cancer.

[16]  S. Mckercher,et al.  Osteopetrosis in mice lacking haematopoietic transcription factor PU.1 , 1997, Nature.

[17]  R. Kyle,et al.  Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma. , 1996, Blood.

[18]  M. Horton,et al.  Antibody to beta3 integrin inhibits osteoclast-mediated bone resorption in the thyroparathyroidectomized rat. , 1996, Endocrinology.

[19]  E. Wagner,et al.  c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. , 1994, Science.

[20]  R. Recker,et al.  Periosteal bone formation stimulated by externally induced bending strains , 1994, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[21]  D. Denhardt,et al.  Osteopontin: a protein with diverse functions , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  B. Klein,et al.  Mechanisms of bone lesions in multiple myeloma. , 1992, Hematology/oncology clinics of North America.

[23]  R. Kyle,et al.  Diagnostic criteria of multiple myeloma. , 1992, Hematology/oncology clinics of North America.

[24]  S. Colucci,et al.  Recognition of osteopontin and related peptides by an alpha v beta 3 integrin stimulates immediate cell signals in osteoclasts. , 1991, The Journal of biological chemistry.

[25]  B. Klein,et al.  Letter to the editor: The bone‐resorbing activity of interleukin‐6 , 1991 .

[26]  Allan Bradley,et al.  Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice , 1991, Cell.

[27]  B. Klein,et al.  The bone-resorbing activity of interleukin-6. , 1991, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[28]  F. Reinholt,et al.  Osteopontin--a possible anchor of osteoclasts to bone. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[29]  M. Jourdan,et al.  Serum levels of interleukin 6, a potent myeloma cell growth factor, as a reflect of disease severity in plasma cell dyscrasias. , 1989, The Journal of clinical investigation.

[30]  P. Lansdorp,et al.  Production of interleukin-1 by bone marrow myeloma cells , 1989 .

[31]  T. Bringman,et al.  Production of lymphotoxin, a bone-resorbing cytokine, by cultured human myeloma cells. , 1987, The New England journal of medicine.

[32]  R. Schrohenloher,et al.  Isolation, characterization, and biosynthesis of a phosphorylated glycoprotein from rat bone. , 1987, The Journal of biological chemistry.

[33]  D. Heinegård,et al.  Cloning and sequence analysis of rat bone sialoprotein (osteopontin) cDNA reveals an Arg-Gly-Asp cell-binding sequence. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[34]  T. Bringman,et al.  Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors , 1986, Nature.

[35]  G. Mundy,et al.  Relation of Osteoclast Activating Factor Production to Extent of Bone Disease in Multiple Myeloma , 1981, British journal of haematology.

[36]  S. Salmon,et al.  A clinical staging system for multiple myeloma correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival , 1975, Cancer.

[37]  G. Mundy,et al.  Evidence for the secretion of an osteoclast stimulating factor in myeloma. , 1974, The New England journal of medicine.

[38]  A. Adatia.  Dental tissues and Burkitt's tumor , 1968 .