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Raloxifene ameliorates detrimental enzymatic and nonenzymatic collagen cross-links and bone strength in rabbits with hyperhomocysteinemia.

AbstractUNLABELLED:
We demonstrate a reduction in enzymatic divalent immature and trivalent pyridinium cross-links and an increase in the nonenzymatic cross-link, pentosidine (Pen), in rabbits with methionine (Met)-induced hyperhomocysteinemia. Such detrimental cross-link formation in bone was ameliorated by raloxifene (RLX) treatment.
INTRODUCTION:
Collagen cross-links are determinants of bone quality. Homocysteine (Hcys) interferes with collagen cross-linking. Because RLX is thought to ameliorate bone quality, we investigated whether RLX ameliorated hyperhomocysteinemia-induced cross-link abnormalities using a Met-rich diet rabbit model.
METHODS:
We divided New Zealand white rabbits into six groups (n = 6 per group): baseline control, sham operation, sham + 1% Met diet, ovariectomy (OVX), 1% Met diet + OVX, OVX + RLX (10 mg/kg/day), and 1% Met diet + OVX + RLX. RLX was administered for 16 weeks. We measured the amount of enzymatic immature and mature pyridinium cross-links and the nonenzymatic cross-link, Pen, and correlated the cross-link content to bone strength.
RESULTS:
Hcys levels were significantly higher in the Met diet groups than in the normal diet groups. Met-fed rabbits with or without OVX showed a significant reduction of enzymatic cross-links, whereas an increase in Pen was observed in Met-fed rabbits with OVX. The cross-link content of the RLX-treated Met-fed rabbits with OVX was restored to similar levels as the sham group, accompanied by an improvement of bone strength.
CONCLUSION:
These results demonstrate that hyperhomocysteinemia reduced bone strength via a reduction of enzymatic cross-links and an increase of nonenzymatic cross-links. RLX may ameliorate hyperhomocysteinemia-induced detrimental cross-linking in rabbits with OVX and may improve bone strength via the amelioration of collagen cross-links.
AuthorsM Saito, K Marumo, S Soshi, Y Kida, C Ushiku, A Shinohara
JournalOsteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA (Osteoporos Int) Vol. 21 Issue 4 Pg. 655-66 (Apr 2010) ISSN: 1433-2965 [Electronic] England
PMID19484165 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Bone Density Conservation Agents
  • Glycation End Products, Advanced
  • Raloxifene Hydrochloride
  • Collagen
  • Arginine
  • Methionine
  • pentosidine
  • Lysine
Topics
  • Animals
  • Arginine (analogs & derivatives, metabolism)
  • Bone Density (drug effects)
  • Bone Density Conservation Agents (therapeutic use)
  • Bone and Bones (physiopathology)
  • Collagen (metabolism)
  • Disease Models, Animal
  • Drug Evaluation, Preclinical (methods)
  • Female
  • Glycation End Products, Advanced (metabolism)
  • Hyperhomocysteinemia (chemically induced, complications, metabolism, physiopathology)
  • Lysine (analogs & derivatives, metabolism)
  • Methionine
  • Osteoporosis (etiology, metabolism, prevention & control)
  • Rabbits
  • Raloxifene Hydrochloride (therapeutic use)
  • Stress, Mechanical

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