Increased expression of receptor activator of nuclear factor-κB ligand in osteoblasts from adolescent idiopathic scoliosis patients with low bone mineral density

Abstract

Persistent generalized low bone mineral density (BMD) has been reported in patients with adolescent idiopathic scoliosis (AIS). However, the exact mechanisms and causes of the low BMD in AIS patients are largely unknown. The purpose of this study was to examine the relationship between the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) levels in osteoblasts (OBs) from AIS patients with low BMD and with comparison made between the patients and controls. Twenty AIS patients and eight age-matched controls were included in the present study. The BMD of lumbar spine and proximal femur was measured in all subjects. OBs from the cancellous bone of each subject was harvested and primarily cultured. The mRNA and protein expression of RANKL and OPG in OBs was detected by RT-PCR and Western blotting. The results showed BMD was lower in AIS patients than in controls. A significantly higher mRNA and protein expression of RANKL was observed in OBs from AIS patients, while no significant difference was found in the expression of OPG between AIS patients and controls. As a result, RANKL/OPG ratio in patients with AIS was remarkably higher than controls. Our study preliminarily demonstrated expression of RANKL was higher in OBs from AIS patients with low BMD as compared with controls, suggesting the unbalanced RANKL/OPG ratio caused by an over-expression of RANKL in OBs may be responsible for the low BMD in AIS patients.

Keywords

adolescent idiopathic scoliosis / bone mineral density / osteoblast / receptor activator of NF-κB ligand / osteoprotegerin

References

[1] SharmaS., GaoX., LondonoD., et al.. Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes. Hum Mol Genet, 2011, 20(7): 1456-1466

[2] BunnellW.P.. The natural history of idiopathic scoliosis before skeletal maturity. Spine (Phila Pa 1976), 1986, 11(8): 773-776

[3] Siu King CheungC., Tak Keung LeeW., Kit TseY., et al.. Abnormal peri-pubertal anthropometric measurements and growth pattern in adolescent idiopathic scoliosis: a study of 598 patients. Spine (Phila Pa 1976), 2003, 28(18): 2152-2157

[4] BurnerW.L., BadgerV.M., ShermanF.C.. Osteoporosis and acquired back deformities. J Pediatr Orthop, 1982, 2(4): 383-385

[5] ChengJ.C., QinL., CheungC.S., et al.. Generalized low areal and volumetric bone mineral density in adolescent idiopathic scoliosis. J Bone Miner Res, 2000, 15(8): 1587-1595

[6] HungV.W., QinL., CheungC.S.K., et al.. Osteopenia: A new prognostic factor of curve progression inadolescent idiopathic scoliosis. J Bone Joint Surg Am, 2005, 87(12): 2709-2716

[7] Sadat-AliM., Al-OthmanA., BubshaitD., et al.. Does scoliosis causes low bone mass? A comparative study between siblings. Eur Spine J, 2008, 17(7): 944-947

[8] ColombiniA., LombardiG., GallieraE., et al.. Plasma and drainage fluid levels of soluble receptor activator of nuclear factor-kB (sRANK), soluble receptor activator of nuclear factor-kB ligand (sRANKL) and osteoprotegerin (OPG) during proximal humerus fracture healing. Int Orthop, 2011, 35(5): 777-782

[9] CappellenD., Luong-NguyenN.H., BongiovanniS., et al.. Transcriptional program of mouse osteoclast differentiation governed by the macrophage colony-stimulating factor and the ligand for the receptor activator of NFkappa B. Biol Chem, 2002, 277(24): 21971-21982

[10] KongY.Y., YoshidaH., SarosiI., et al.. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature, 1999, 397(6717): 315-323

[11] HofbauerL.C., KhoslaS., DunstanC.R., et al.. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res, 2000, 15(1): 2-12

[12] GurbanC.V., MederleO.. The OPG/RANKL system and zinc ions are promoters of bone remodeling by osteoblast proliferation in postmenopausal osteoporosis. Rom J Morphol Embryol, 2011, 52(3): 1113-1119

[13] HofbauerL.C., GoriF., RiggsB.L., et al.. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by gluco-corticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology, 1999, 140(10): 4382-4389

[14] García PalaciosV., RobinsonL.J., BorysenkoC.W., et al.. Negative regulation of RANKL-induced osteoclastic differentiation in RAW264.7 Cells by estrogen and phytoestrogens. J Biol Chem, 2005, 280(14): 13720-13727

[15] HsuH., LaceyD.L., DunstanC.R., et al.. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A, 1999, 96(7): 3540-3545

[16] BjureJ., GrimbyG., NachemsonA.. Correction of body height in predicting spirometric values in scoliotic patients. Scand J Clin Lab Invest, 1968, 21(2): 191-192

[17] QiuY., SunX., ChengJ.C., et al.. Bone mineral accrual in osteopenic and non-osteopenic girls with idiopathic scoliosis during bracing treatment. Spine (Phila Pa 1976), 2008, 33(15): 1682-1689

[18] CookS.D., HardingA.F., MorganE.L., et al.. Trabecular bone mineral density in idiopathic scoliosis. J Pediatr Orthop, 1987, 7(2): 168-174

[19] ChengJ.C., GuoX.. Osteopenia in adolescent idiopathic scoliosis. A primary problem or secondary to the spinal deformity?. Spine (Phila Pa 1976), 1997, 22(15): 1716-1721

[20] ChengJ.C., GuoX., SherA.H.. Persistent osteopenia in adolescent idiopathic scoliosis. A longitudinal follow up study. Spine (Phila Pa 1976), 1999, 24(12): 1218-1222

[21] LeeW.T., CheungC.S., TseY.K., et al.. Association of osteopenia with curve severity in adolescent idiopathic scoliosis: a study of 919 girls. Osteoporos Int, 2005, 16(12): 1924-1932

[22] LamT.P., TseY.K., HungV.W., et al.. Adolescents with idiopathic scoliosis are not osteoporotic. Spine (Phila Pa 1976), 2010, 35(1): 130-131

[23] SzalayE.A., BoschP., SchwendR.M., et al.. Adolescents with idiopathic scoliosis are not osteoporotic. Spine (Phila Pa 1976), 2008, 33(7): 802-806

[24] QiuY., SunX., QiuX., et al.. Decreased circulating leptin level and its association with body and bone mass in girls with adolescent idiopathic scoliosis. Spine (Phila Pa 1976), 2007, 32(24): 2703-2710

[25] GuoX., ChauW.W., ChanY.L., et al.. Relative anterior spinal overgrowth in adolescent idiopathic scoliosis. Results of disproportionate endochondral-membranous bone growth. J Bone Joint Surg Br, 2003, 85(7): 1026-1031

[26] OtteA., Mueller-BrandJ., DellasS., et al.. Yttrium-90-labelled somatostatin-analogue for cancer treatment. Lancet, 1998, 351(9100): 417-418