title: Increased expression of IL-6 and RANK mRNA in human trabecular bone from fragility fracture of the femoral neck.
abstract: Previous studies have implicated pro-inflammatory cytokines in the bone loss of estrogen deficiency. The aim of this study was to investigate the expression of key regulatory molecules of bone remodeling in the trabecular bone microenvironment in osteoporosis. Bone samples were taken from the intertrochanteric region of the proximal femur of patients undergoing total hip arthroplasty for a subcapital fragility fracture of the femoral neck (#NOF). For comparison, samples were taken from age-matched control individuals at routine autopsy. Expression of RANKL, RANK, osteoprotegerin (OPG), IL-6, IL-11, osteocalcin (OCN), and calcitonin receptor (CTR) messenger RNA (mRNA) species were analyzed and the data were nonparametrically distributed. The median expression of the proresorptive genes, RANK and IL-6, were significantly elevated in the fracture group compared to an age-matched control group (2.2 [1.9-2.9; 25th-75th percentiles] > 1.0 [0.4-2.1], P < 0.03; 3.9 [1.8-6.2] > 0.8 [0.7-1.5], P < 0.002, respectively). In contrast, there were no significant differences in expression of RANKL, OPG, CTR, or OCN mRNA between the #NOF and control groups. The median RANKL/OPG mRNA ratio was significantly greater in hip fracture bone than in bone from controls (4.8 [3.8-7.6] > 3.2 [2.1-4.0], P < 0.05). IL-6 mRNA levels associated strongly with RANKL mRNA levels in the #NOF group (r = 0.77, P < 0.001), but not in the control group. A strong positive association was found between IL-11 mRNA levels and RANKL mRNA levels in the #NOF group (r = 0.81, P < 0.001), consistent with the apparent coordinated regulation of IL-6 and IL-11 in bone samples from the #NOF group (r = 0.93, P < 0.0001). These data suggest a relative increase in the expression of the molecular promoters of osteoclast formation and activity in #NOF bone, which may lead to the imbalance between bone formation and resorption associated with fragility fracture.
authors.affiliation: Division of Tissue Pathology, Institute of Medical and Veterinary Science, Adelaide, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Tsangari
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.forename: Julia S
authors.initials: JS
authors.lastname: Kuliwaba
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Atkins
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Fazzalari
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016723:Bone Remodeling; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005265:Femoral Neck Fractures / Q000378:metabolism* / Q000473:pathology; D005269:Femur / Q000378:metabolism* / Q000473:pathology; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D017370:Interleukin-11 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D015675:Osteocalcin / Q000096:biosynthesis / Q000235:genetics; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D053246:Receptor Activator of Nuclear Factor-kappa B; D018003:Receptors, Calcitonin / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D017370:Interleukin-11; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D018003:Receptors, Calcitonin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D015675:Osteocalcin