title: Structurally different bisphosphonates exert opposing effects on alkaline phosphatase and mineralization in marrow osteoprogenitors.
abstract: 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.
authors.affiliation: Laboratory of Experimental Surgery, Hadassah Medical Center, Hebrew University of Jerusalem, Israel.
authors.forename: B Y
authors.initials: BY
authors.lastname: Klein
authors.forename: H
authors.initials: H
authors.lastname: Ben-Bassat
authors.forename: E
authors.initials: E
authors.lastname: Breuer
authors.forename: V
authors.initials: V
authors.lastname: Solomon
authors.forename: G
authors.initials: G
authors.lastname: Golomb
mesh_terms: 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
chemical_list: 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