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Increased Osteoclast Activity in the Presence of Increased Homocysteine Concentrations

¹ Abteilung für Klinische Chemie und Laboratoriumsmedizin/Zentrallabor and ² Klinik für Innere Medizin I, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
³ Department of Human Anatomy and Histology, University of Bari, Bari, Italy.

^aAddress correspondence to this author at: Abteilung für Klinische Chemie und Laboratoriumsmedizin/Zentrallabor, Universitätsklinikum des Saarland, D-66421 Homburg/Saar, Germany. Fax 49-6841-1630703; e-mail kchwher{at}uniklinik-saarland.de.

Background: Increased plasma homocysteine (HCY) may be an independent risk factor for osteoporotic fractures and therefore may also adversely affect bone metabolism. We analyzed the effect of HCY on human osteoclast (OC) activity.

Methods: We cultured peripheral blood mononuclear cells from 17 healthy male donors [median (SD) age, 30 (5) years] for 20 days with 25 µg/L macrophage-colony-stimulating factor (days 0–11), 20 µg/L receptor-activator of nuclear factor-B ligand (days 6–20), and 4 different concentrations of HCY (0, 10, 50, and 100 µmol/L; days 0–20). For control purposes, cysteine and glutathione were tested in equimolar concentrations. OCs were identified as large, multinucleated cells with tartrate-resistant acid phosphatase (TRAP) activity and surface vitronectin receptors. We quantified OC activity by measuring TRAP activity. We analyzed cathepsin K (CP-K) activity in 9 donor samples and estimated the dentine-resorbing activity on standard dentine slices in 3 samples.

Results: After 20 days of culture, most cells were fully differentiated OCs. TRAP activity increased with increasing HCY concentrations (P <0.001). HCY concentrations of 10, 50, and 100 µmol/L stimulated TRAP activity by 20%, 15%, and 42%. Additionally, HCY stimulated CP-K activity (P = 0.005): in the presence of 100 µmol/L HCY, CP-K activity was 38% higher than in controls (P = 0.002). Bone-resorbing activity was significantly increased in cultures with 50 and 100 µmol/L HCY. Cysteine and glutathione significantly decreased TRAP and CP-K activity.

Conclusions: Increased HCY concentrations specifically stimulate OC activity in vitro, suggesting a mechanistic role of HCY for bone resorption. Future studies clarifying the mechanistic role of increased HCY concentrations in osteoporosis could have interesting therapeutic implications.

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				H. Refsum, E. Nurk, A. D. Smith, P. M. Ueland, C. G. Gjesdal, I. Bjelland, A. Tverdal, G. S. Tell, O. Nygard, and S. E. Vollset The Hordaland Homocysteine Study: A Community-Based Study of Homocysteine, Its Determinants, and Associations with Disease J. Nutr., June 1, 2006; 136(6): 1731S - 1740S. [Abstract] [Full Text] [PDF]