title: Homocysteine mediated decrease in bone blood flow and remodeling: role of folic acid.
abstract: Deficiencies in folate lead to increased serum concentrations of homocysteine (Hcy), which is known as hyperhomocysteinemia (HHcy), is associated with bone disorders. Although, Hcy accumulates collagen in bone and contribute to decrease in bone strength. The mechanism of Hcy induced bone loss and remodeling is unclear. Therefore, the present study was aimed to determine the role of folic acid (FA) in genetically HHcy-associated decrease in bone blood flow and remodeling. Wild type (WT) and cystathionine-β-synthase heterozygous (CBS+/-) mice were used in this study and supplemented with or without FA (300 mg/kg, Hcy reducing agent) in drinking water for 6 weeks. The tibial bone blood flow was measured by laser Doppler and ultrasonic flow probe method. The tibial bone density (BD) was assessed by dual energy X-ray absorptiometry. The bone homogenates were analyzed for oxidative stress, NOX-4 as oxidative marker and thioredoxin-1 (Trx-1) as anti-oxidant marker, bone remodeling (MMP-9) and bio-availability of nitric oxide (eNOS/iNOS/NO) by Western blot method. The results suggested that there was decrease in tibial blood flow in CBS+/- mice. The BD was also reduced in CBS+/- mice. There was an increase in NOX-4, iNOS, MMP-9 protein as well as MMP-9 activity in CBS+/- mice and decrease in Trx-1, eNOS protein levels, in part by decreasing NO bio-availability in CBS+/- mice. Interestingly, these effects were ameliorated by FA and suggested that FA supplementation may have therapeutic potential against genetically HHcy induced bone loss.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, Kentucky 40202, USA. n0tyag01@louisville.edu
authors.forename: Neetu
authors.initials: N
authors.lastname: Tyagi
authors.forename: Madhavi
authors.initials: M
authors.lastname: Kandel
authors.forename: Charu
authors.initials: C
authors.lastname: Munjal
authors.forename: Natia
authors.initials: N
authors.lastname: Qipshidze
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Vacek
authors.forename: Sathnur B
authors.initials: SB
authors.lastname: Pushpakumar
authors.forename: Naria
authors.initials: N
authors.lastname: Metreveli
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
mesh_terms: D000818:Animals; D015519:Bone Density; D016723:Bone Remodeling; D005492:Folic Acid / Q000502:physiology*; D006710:Homocysteine / Q000502:physiology*; D020138:Hyperhomocysteinemia / Q000150:complications*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D010024:Osteoporosis / Q000209:etiology*; D018384:Oxidative Stress; D012039:Regional Blood Flow; D013977:Tibia / Q000098:blood supply; D016909:Tibial Arteries / Q000502:physiology
chemical_list: D006710:Homocysteine; D009569:Nitric Oxide; D005492:Folic Acid; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse