Inhibitor of DASH proteases affects expression of adhesion molecules in osteoclasts and reduces myeloma growth and bone disease

• Published in: British journal of haematology Vol. 145; no. 6; pp. 775 - 787
• Main Authors: Pennisi, Angela, Li, Xin, Ling, Wen, Khan, Sharmin, Gaddy, Dana, Suva, Larry J., Barlogie, Bart, Shaughnessy, John D., Aziz, Nazneen, Yaccoby, Shmuel
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-06-2009; Blackwell
• Subjects: Alkaline Phosphatase - metabolism; Animals; Biological and medical sciences; Biomarkers, Tumor - blood; Bone Density - drug effects; Bone Resorption - drug therapy; Bone Resorption - metabolism; Boronic Acids - therapeutic use; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Differentiation - drug effects; Coculture Techniques; Dipeptides - therapeutic use; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - antagonists & inhibitors; DPPIV proteases; fibroblast activation protein; Gene Expression; Gene Expression Profiling - methods; Hematologic and hematopoietic diseases; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulin Light Chains - blood; Immunoglobulinopathies; Immunohistochemistry; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, SCID; microenvironment; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; myeloma; NF-kappa B - metabolism; Oligonucleotide Array Sequence Analysis; osteoclasts; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoclasts - pathology; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Immunopathology; DPPIV proteases; Hematology; Enzyme; Growth; Diseases of the osteoarticular system; Cell adhesion molecule; B cell neoplasm; Malignant hemopathy; Osteoclast; Lymphoid neoplasm; Microenvironment; Myeloma; Fibroblast activation protein; Osteoarticular system; Peptidases; Immunoglobulinopathy; Lymphoproliferative syndrome; osteoclasts; Hydrolases; Bone; Protease inhibitor; Cancer
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2009.07696.x

Summary
Dipeptidyl peptidase (DPP) IV activity and/or structure homologues (DASH) are serine proteases implicated in tumourigenesis. We previously found that a DASH protease, fibroblast activation protein (FAP), was involved in osteoclast‐induced myeloma growth. Here we further demonstrated expression of various adhesion molecules in osteoclasts cultured alone or cocultured with myeloma cells, and tested the effects of DASH inhibitor, PT‐100, on myeloma cell growth, bone disease, osteoclast differentiation and activity, and expression of adhesion molecules in osteoclasts. PT‐100 had no direct effects on viability of myeloma cells or mature osteoclasts, but significantly reduced survival of myeloma cells cocultured with osteoclasts. Real‐time PCR array for 85 adhesion molecules revealed upregulation of 17 genes in osteoclasts after coculture with myeloma cells. Treatment of myeloma/osteoclast cocultures with PT‐100 significantly downregulated 18 of 85 tested genes in osteoclasts, some of which are known to play roles in tumourigenesis and osteoclastogenesis. PT‐100 also inhibited osteoclast differentiation and subsequent pit formation. Resorption activity of mature osteoclasts and differentiation of osteoblasts were not affected by PT‐100. In primary myelomatous severe combined immunodeficient (SCID)‐hu mice PT‐100 reduced osteoclast activity, bone resorption and tumour burden. These data demonstrated that DASH proteases are involved in myeloma bone disease and tumour growth.