Top

Osteoporosis International

Published in:

01-04-2010 | Original Article

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

Authors: M. Saito, K. Marumo, S. Soshi, Y. Kida, C. Ushiku, A. Shinohara

Published in: Osteoporosis International | Issue 4/2010

Abstract

Summary

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.

Seeman E, Delmas PD (2006) Bone quality—the material and structural basis of bone strength and fragility. N Engl J Med 354:2250–2261CrossRefPubMed

Burr DB (2002) Bone material properties and mineral matrix contributions to fracture risk or age in women and men. J Musculoskelet Neuronal Interact 2:201–204PubMed

Paschalis EP, Shane E, Lyritis G et al (2004) Bone fragility and collagen cross-links. J Bone Miner Res 19:2000–2004CrossRefPubMed

Vashishth D (2007) The role of the collagen matrix in skeletal fragility. Curr Osteoporos Rep 5:62–66CrossRefPubMed

Wang X, Shen X, Li X et al (2002) Age-related changes in the collagen network and toughness of bone. Bone 31:1–7CrossRefPubMed

Saito M, Fujii K, Mori Y et al (2006) Role of collagen enzymatic and glycation induced cross-links as a determinant of bone quality in spontaneously diabetic WBN/Kob rats. Osteoporos Int 17:1514–1523CrossRefPubMed

Oxlund H, Mosekilde L, Ortoft G (1996) Reduced concentration of collagen reducible crosslinks in human trabecular bone with respect to age and osteoporosis. Bone 19:479–484CrossRefPubMed

Banse X, Sims TJ, Bailey AJ (2002) Mechanical properties of adult vertebral cancellous bone: correlation with collagen intermolecular cross-links. J Bone Miner Res 17:1621–1628CrossRefPubMed

Paschalis EP, Recker R, Dicarlo E et al (2003) Distribution of collagen cross-links in normal human trabecular bone. J Bone Miner Res 18:1942–1946CrossRefPubMed

10.

Saito M, Soshi S, Fujii K (2003) Effect of hyper- and microgravity on collagen post-translational controls of MC3T3-E1 osteoblasts. J Bone Miner Res 18:1695–1705CrossRefPubMed

11.

Uzawa K, Grzesik WJ, Nishiura T et al (1999) Differential expression of human lysyl hydroxylase genes, lysyl hydroxylation, and cross-linking of type I collagen during osteoblastic differentiation in vitro. J Bone Miner Res 14:1272–1280CrossRefPubMed

12.

McLean RR, Jacques PF, Selhub J et al (2004) Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 350:2042–2049CrossRefPubMed

13.

van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM et al (2004) Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 35:2033–2041CrossRef

14.

McKusick VA (1966) Heritable disorders of connective tissue, 3rd edn. C.V. Mosby, St. Louis, p 155

15.

Lubec B, Fang-Kircher S, Lubec T et al (1996) Evidence for McKusick's hypothesis of deficient collagen cross-linking in patients with homocystinuria. Biochim Biophys Acta 13:159–162

16.

Saito M, Sohsi S, Tanaka T et al (2004) Intensity-related differences in collagen post-translational modification in MC3T3-E1 osteoblasts after exposure to low and high intensity pulsed ultrasound. Bone 35:644–655CrossRefPubMed

17.

McCarthy AD, Etcheverry SB, Bruzzone L et al (2001) Non-enzymatic glycation of a type I collagen matrix: effect on osteoblastic development and oxidative stress. BMC Cell Biol 2:16CrossRefPubMed

18.

Garnero P, Borel O, Gineyts E et al (2006) Extracellular post-translational modifications of collagen are major determinants of biomechanical properties of fetal bovine cortical bone. Bone 38:300–309CrossRefPubMed

19.

Blouin S, Thaler HW, Korninger C et al (2009) Bone matrix quality and plasma homocysteine levels. Bone 44:959–964CrossRefPubMed

20.

Saito M, Fujii K, Marumo K (2006) Degree of mineralization-related collagen crosslinking in the femoral neck cancellous bone in cases of hip fracture and controls. Calcif Tissue Int 79:160–168CrossRefPubMed

21.

Delmas PD, Li Z, Cooper C (2004) Relationship between changes in bone mineral density and fracture risk reduction with antiresorptive drugs: some issues with meta-analyses. J Bone Miner Res 19:330–337CrossRefPubMed

22.

Recker RR, Kendler D, Recknor CP et al (2007) Comparative effects of raloxifene and alendronate on fracture outcomes in post-menopausal women with low bone mass. Bone 40:843–851CrossRefPubMed

23.

Allen MR, Gynets E, Leeming DJ et al (2008) Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra. Osteoporos Int 19:329–337CrossRefPubMed

24.

Walsh BW, Paul S, Wild RA et al (2000) The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab 85:214–218CrossRefPubMed

25.

De Leo V, la Marca A, Morgante G et al (2001) Randomized control study of the effects of raloxifene on serum lipids and homocysteine in older women. Am J Obstet Gynecol 84:350–353CrossRef

26.

Toborek M, Kopieczna-Grzebieniak E, Drozdz M et al (1995) Increases lipid peroxidation as a mechanism of methionine-induced atherosclerosis in rabbit. Atherosclerosis 115:217–224CrossRefPubMed

27.

Bjarnason NH, Haarbo J, Byrjalsen I et al (2000) Raloxifene reduces atherosclerosis: studies of optimized raloxifene doses in ovariectomized, cholesterol-fed rabbits. Clin Endocrinol 52:225–233CrossRef

28.

Araki A, Sako Y (1987) Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 422:43–52CrossRefPubMed

29.

Saito M, Marumo K, Fujii K et al (1997) Single column high-performance liquid chromatographic-fluorescence detection of immature, mature and senescent cross-links of collagen. Anal Biochem 253:26–32CrossRefPubMed

30.

Nonaka K, Fukuda S, Aoki K et al (2006) Regional distinctions in cortical bone mineral density measured by pQCT can predict alterations in material properties at the tibial diaphysis of the Cynomolgus monkey. Bone 38:265–272CrossRefPubMed

31.

Manabe T, Mori S, Mashiba T et al (2007) Human parathyroid hormone (1–34) accelerates natural fracture healing process in the femoral osteotomy model of cynomolgus monkeys. Bone 40:1475–1482CrossRefPubMed

32.

Turner CH, Akhter MP, Heaney RP (1992) The effects of fluoridated water on bone strength. J Orthop Res 10:581–587CrossRefPubMed

33.

Castaneda S, Calvo E, Largo R et al (2008) Characterization of a new experimental model of osteoporosis in rabbits. J Bone Miner Metab 26:53–59CrossRefPubMed

34.

Shukla N, Koupparis A, Jones RA et al (2006) Penicillamine administration reverses the inhibitory effect of hyperhomocysteinaemia on endothelium-dependent relaxation and superoxide formation in the aorta of the rabbit. Eur J Pharmacol 531:201–208CrossRefPubMed

35.

Narin F, Narin N, Akcakus M et al (2002) The effect of folic acid, vitamin B6 and vitamin B12 on the homocysteine levels in rabbits fed by methionine-enriched diets. Tohoku J Exp Med 198:99–105CrossRefPubMed

36.

Saito M, Mori S, Mashiba T et al (2008) Collagen maturity, glycation induced-pentosidine, and mineralization are increased following 3-year treatment with incadronate in dogs. Osteoporos Int 19:1343–1354CrossRefPubMed

37.

Bellino FL (2000) Nonprimate animal models of menopause: workshop report. Menopause 7:14–24CrossRefPubMed

38.

Silva MJ, Brodt MD, Wopenka B et al (2006) Decreased collagen organization and content are associated with reduced strength of demineralized and intact bone in the SAMP6 mouse. J Bone Miner Res 21:78–88CrossRefPubMed

39.

Saito M, Fujii K, Soshi S et al (2006) Reductions in degree of mineralization and enzymatic collagen cross-links and increases in glycation induced pentosidine in the femoral neck cortex in cases of femoral neck fracture. Osteoporos Int 17:986–995CrossRefPubMed

40.

Shiraki M, Urano T, Kuroda T et al (2008) The synergistic effect of bone mineral density and methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T) on fracture. J Bone Miner Metab 26:595–602CrossRefPubMed

41.

Turecek C, Fratzl-Zelman N, Rumpler M (2008) Collagen cross-linking influences osteoblastic differentiation. Calcif Tissue Int 82:392–400CrossRefPubMed

42.

Ozasa H, Tominaga T, Nishimura T et al (1981) Lysyl oxidase activity in the mouse uterine cervix is physiologically regulated by estrogen. Endocrinology 109:618–621CrossRefPubMed

43.

Hak AE, Polderman KH, Westendorp IC et al (2000) Increased plasma homocysteine after menopause. Atherosclerosis 149:163–168CrossRefPubMed

44.

Russo GT, Di Benedetto A, Alessi E et al (2008) Menopause modulates homocysteine levels in diabetic and non-diabetic women. J Endocrinol Invest 31:546–551PubMed

45.

Herrmann M, Tami A, Wildemann B et al (2008) Hyperhomocysteinemia induces a tissue specific accumulation of homocysteine in bone by collagen binding and adversely affects bone. Bone 44:467–475CrossRefPubMed

46.

Herrmann M, Peter Schmidt J, Umanskaya N et al (2007) The role of hyperhomocysteinemia as well as folate, vitamin B(6) and B(12) deficiencies in osteoporosis: a systematic review. Clin Chem Lab Med 45:1621–1632CrossRefPubMed

47.

Raposo B, Rodriguez C, Martinez-Gonzalez J et al (2004) High levels of homocysteine inhibit lysyl oxidase (LOX) and down regulate LOX expression in vascular endothelial cells. Atherosclerosis 177:1–8CrossRefPubMed

48.

Kang HA, Trelstad RL (1973) A collagen defect in homocystinuria. J Clin Invest 52:2571–2578CrossRefPubMed

49.

Reiser KM (1991) Nonenzymatic glycation of collagen in aging and diabetes. Proc Soc Exp Biol Med 196:17–29PubMed

50.

Eberhardt RT, Forgione MA, Cap A et al (2000) Endothelial dysfunction in a murine model of mild hyper homocyst(e) inemia. J Clin Invest 106:483–491CrossRefPubMed

51.

Castelo-Branco C, Sanjuan A, Casals E et al (2004) Raloxifene inhibits cholesterol aortic content but not atherosclerotic plaque size in oophorectomised cholesterol-fed rabbits. J Obstet Gynaecol 24:47–51CrossRefPubMed

52.

Khastgir G, Studd J, Holland N et al (2001) Anabolic effect of long-term estrogen replacement on bone collagen in elderly postmenopausal women with osteoporosis. Osteoporos Int 12:465–470CrossRefPubMed

53.

Paschalis EP, Boskey AL, Kassem M et al (2003) Effect of hormone replacement therapy on bone quality in early postmenopausal women. J Bone Miner Res 18:955–959CrossRefPubMed

54.

Faibish D, Ott SM, Bosky AL (2006) Mineral changes in osteoporosis—a review. Clin Orthop Relat Res 443:28–38CrossRefPubMed

55.

Yang NN, Bryant HU, Hardikar S et al (1996) Estrogen and raloxifene stimulate transforming growth factor-beta 3 gene expression in rat bone: a potential mechanism for estrogen- or raloxifene-mediated bone maintenance. Endocrinology 137:2075–2084CrossRefPubMed

56.

Feres-Filho EJ, Choi YJ, Han X et al (1995) Pre- and post-translational regulation of lysyl oxidase by transforming growth factor-beta 1 in osteoblastic MC3T3-E1 cells. J Biol Chem 270:30797–30803CrossRefPubMed

57.

Shibata Y, Abiko Y, Moriya Y et al (1993) Effects of transforming growth factor-beta on collagen gene expression and collagen synthesis level in mineralizing cultures of osteoblast-like cell line, MC3T3-E1. Int J Biochem 25:239–245CrossRefPubMed

58.

Helvering LM, Liu R, Kulkarni N et al (2005) Expression profiling of rat femur revealed suppression of bone formation genes by treatment with alendronate and estrogen but not raloxifene. Mol Pharmacol 68:1225–1238CrossRefPubMed

59.

Mann V, Huber C, Kogianni G et al (2007) The antioxidant effect of estrogen and selective estrogen receptor modulators in the inhibition of osteocyte apoptosis in vitro. Bone 40:674–684CrossRefPubMed

60.

Brady JD, Robins SP (2001) Structural characterization of pyrrolic cross-links in collagen using a biotinylated Ehrlich's reagent. J Biol Chem 276:18812–18818CrossRefPubMed

Title: Raloxifene ameliorates detrimental enzymatic and nonenzymatic collagen cross-links and bone strength in rabbits with hyperhomocysteinemia
Authors: M. Saito
K. Marumo
S. Soshi
Y. Kida
C. Ushiku
A. Shinohara
Publication date: 01-04-2010
Publisher: Springer-Verlag
Published in: Osteoporosis International / Issue 4/2010
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-009-0980-4

At a glance: The STEP trials

Springer Medicine

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

Abstract

Summary

Introduction

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 4/2010

Self-reported preclinical mobility limitation and fall history as predictors of future falls in older women: prospective cohort study

Bisphosphonates and osteoporotic fractures: a cross-design synthesis of results among compliant/persistent postmenopausal women in clinical practice versus randomized controlled trials

Peripubertal estrogen levels and physical activity affect femur geometry in young adult women

Treatment thresholds for osteoporosis in men on androgen deprivation therapy: T-score versus FRAX™

Maternal and fetal outcome after long-term bisphosphonate exposure before conception

Sarcopenia: etiology, clinical consequences, intervention, and assessment