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


BACKGROUND
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.


CONCLUSIONS
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.
Saito
M
M
Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan. xlink67@gol.com
Marumo
K
K
Soshi
S
S
Kida
Y
Y
Ushiku
C
C
Shinohara
A
A
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001842:Bone and Bones / Q000503:physiopathology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008715:Methionine; D010024:Osteoporosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D011817:Rabbits; D020849:Raloxifene Hydrochloride / Q000627:therapeutic use*; D013314:Stress, Mechanical
D050071:Bone Density Conservation Agents; D017127:Glycation End Products, Advanced; D020849:Raloxifene Hydrochloride; D003094:Collagen; D001120:Arginine; D008715:Methionine; C062187:pentosidine; D008239:Lysine