Structurally different bisphosphonates exert opposing effects on alkaline phosphatase and mineralization in marrow osteoprogenitors.
Bisphosphonates (BPs) are inhibitors of bone resorption and soft tissue calcification. The biological effects of the BPs in calcium-related disorders are attributed mainly to their incorporation in bone, enabling direct interaction with osteoclasts and/or osteoblasts through a variety of biochemical pathways. Structural differences account for the considerable differences in the pharmacological activity of BPs. We compared the effects of two structurally different compounds, alendronate and 2-(3'-dimethylaminopyrazinio)ethylidene-1,1-bisphosphonic acid betaine (VS-6), in an osteoprogenitor differentiation system. The BPs were examined in a bone marrow stromal-cell culture system, which normally results in osteoprogenitor differentiation. The drugs were present in the cultures from days 2 to 11 of osteogenic stimulation, a period estimated as being comparable to the end of proliferation and the matrix-maturation stages. We found that the two different BPs have opposing effects on specific alkaline phosphatase (ALP) activity, on stromal-cell proliferation, and on cell-mediated mineralization. These BPs differentially interact with cell-associated phosphohydrolysis, particularly at a concentration of 10(-2) of ALP Km, in which alendronate inhibits whereas VS-6 did not inhibit phosphatase activity. VS-6 treatment resulted in similar and significantly increased mineralization at 10 and 1 microM drug concentrations, respectively. In contrast, mineralization was similar to control, and significantly decreased at 10 and 1 microM drug concentrations, respectively, under alendronate treatment.
Klein
B Y
BY
Laboratory of Experimental Surgery, Hadassah Medical Center, Hebrew University of Jerusalem, Israel.
Ben-Bassat
H
H
Breuer
E
E
Solomon
V
V
Golomb
G
G
D019386:Alendronate / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000187:drug effects*; D000818:Animals; D001622:Betaine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004164:Diphosphonates / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006868:Hydrolysis / Q000187:drug effects; D009596:Nitrophenols / Q000037:antagonists & inhibitors / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013234:Stem Cells / Q000166:cytology*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
C110765:2-(3'-dimethylaminopyrazinio)ethylidene-1,1-bisphosphonic acid betaine; D004164:Diphosphonates; D009596:Nitrophenols; D009943:Organophosphorus Compounds; C008644:nitrophenylphosphate; D001622:Betaine; D000469:Alkaline Phosphatase; D019386:Alendronate