title: Critical molecular regulators, histomorphometric indices and their correlations in the trabecular bone in primary hip osteoarthritis.
abstract: OBJECTIVE
  This study examined differential gene expression, histomorphometric indices and relationships between these, in femoral trabecular bone from osteoarthritis (OA) patients and control (CTL) subjects, with the aim of identifying potential molecular drivers consistent with changes in structural and remodelling indices in the OA pathology.
  
  
  METHODS
  Bone samples from the intertrochanteric (IT) region were obtained from age and sex-matched cohorts of 23 primary hip OA patients and 21 CTL subjects. Real-time polymerase chain reaction (PCR) and histomorphometric analysis were performed on each sample and correlations between gene expression and histomorphometric variables determined.
  
  
  RESULTS
  Alterations in gene expression, structural indices and correlations between these were found in OA bone compared to CTL. In OA bone, expression of critical regulators of osteoblast differentiation (TWIST1) and function (PTEN, TIMP4) were decreased, while genes associated with inflammation (SMAD3, CD14) were increased. Bone structural and formation indices (BV/TV, Tb.N, OS/BS) were increased, whereas resorption indices (ES/BS, ES/BV) were decreased. Importantly, significant correlations in CTL bone between CTNNB1 expression and formation indices (OS/BS, OS/BV, OV/BV) were absent in OA bone, indicating altered WNT/β-catenin signalling. TWIST1 expression and BV/TV were correlated in CTL bone, but not in OA bone, consistent with altered osteoblastogenesis in OA. Matrix metalloproteinase 25 (MMP25) expression and remodelling indices (ES/BS, ES/BV, ES/TV) were correlated only in OA pointing to aberrant bone remodelling in this pathology.
  
  
  CONCLUSIONS
  These findings indicate an altered state of osteoblast differentiation and function in OA driven by several key molecular regulators. In association with this differential gene expression, an altered state of both trabecular bone remodelling and resulting microarchitecture were also observed, further characterising the pathogenesis of primary hip OA.
authors.affiliation: Bone & Joint Research Laboratory, Surgical Pathology, SA Pathology, Adelaide, South Australia, Australia. Duminda.Kumarasinghe@health.sa.gov.au
authors.forename: D D
authors.initials: DD
authors.lastname: Kumarasinghe
authors.forename: E
authors.initials: E
authors.lastname: Perilli
authors.forename: H
authors.initials: H
authors.lastname: Tsangari
authors.forename: L
authors.initials: L
authors.lastname: Truong
authors.forename: J S
authors.initials: JS
authors.lastname: Kuliwaba
authors.forename: B
authors.initials: B
authors.lastname: Hopwood
authors.forename: G J
authors.initials: GJ
authors.lastname: Atkins
authors.forename: N L
authors.initials: NL
authors.lastname: Fazzalari
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019644:Arthroplasty, Replacement, Hip; D015415:Biomarkers / Q000378:metabolism; D016723:Bone Remodeling / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D015331:Cohort Studies; D005260:Female; D005269:Femur / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D015207:Osteoarthritis, Hip / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D010006:Osteoblasts / Q000473:pathology / Q000502:physiology; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger