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Homocysteine Enhances Bone Resorption by Stimulation of Osteoclast Formation and Activity Through Increased Intracellular ROS Generation
Author(s) -
Koh JungMin,
Lee YoungSun,
Kim Yang Soon,
Kim Duk Jae,
Kim HongHee,
Park JoongYeol,
Lee KiUp,
Kim Ghi Su
Publication year - 2006
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.060406
Subject(s) - osteoclast , bone resorption , medicine , endocrinology , intracellular , p38 mitogen activated protein kinases , resorption , chemistry , mapk/erk pathway , microbiology and biotechnology , kinase , biology , receptor
Abstract Hyperhomocystinemia is a modifiable risk factor for osteoporosis and fracture. Physiologic concentrations of Hcy directly activate osteoclast formation and activity through stimulation of p38 MAPK and integrin β 3 . The effects of Hcy were mediated by generation of intracellular ROS. Introduction: Hyperhomocysteinemia is a modifiable risk factor for osteoporosis and its related bone fractures. It has been reported that bone resorption and turnover rate were increased in hyperhomocystinemia. Using mouse bone marrow cells, we examined the direct effects of homocysteine (Hcy) on osteoclast formation and activity. Materials and Methods: Osteoclast formation was determined by TRACP staining and TRACP activity. Intracellular reactive oxygen species (ROS) generation was measured using a fluorescent probe, dichlorodihydrofluorescein diacetate. Intracellular signaling cascades of p38 mitogen‐activated protein kinase (MAPK), extracellular signal‐regulated kinase (ERK), c‐Jun N‐terminal kinase (JNK), and NF‐κB were measured by Western blotting. Integrin β 3 mRNA levels were measured by RT‐PCR. Actin ring formation and bone resorption assays were also performed. Results: Physiologic concentrations of Hcy upregulated TRACP + multinucleated cells and TRACP activity, stimulated actin ring formation, and increased the number of nuclei per cell and the level of expression of integrin β 3 mRNA. In addition, Hcy increased bone resorption and stimulated p38 MAPK activity and intracellular reactive oxygen species (ROS) generation. All of these Hcy‐induced changes were blocked by pretreatment with the antioxidant, N‐acetyl cysteine. Conclusions: Hcy directly activates osteoclast formation and activity through increased generation of intracellular ROS. These findings suggest that, in individuals with mild to moderate hyperhomocystinemia, increased bone resorption by osteoclasts may contribute to osteoporosis and that an antioxidant may attenuate bone loss in these individuals.