title: Low osteocalcin/collagen type I bone gene expression ratio is associated with hip fragility fractures.
abstract: BACKGROUND
  Osteocalcin (OC) is the most abundant non-collagenous bone protein and is determinant for bone mineralization. We aimed to compare OC bone expression and serum factors related to its carboxylation in hip fragility fracture and osteoarthritis patients. We also aimed to identify which of these factors were associated with worse mechanical behavior and with the hip fracture event.
  
  
  METHODS
  In this case-control study, fragility fracture patients submitted to hip replacement surgery were evaluated and compared to a group of osteoarthritis patients submitted to the same procedure. Fasting blood samples were collected to assess apolipoproteinE (apoE) levels, total OC and undercarboxylated osteocalcin (ucOC), vitamin K, LDL cholesterol, triglycerides and bone turnover markers. The frequency of the apoε4 isoform was determined. Femoral epiphyses were collected and trabecular bone cylinders drilled in order to perform compression mechanical tests. Gene expression of bone matrix components was assessed by quantitative RT-PCR analysis.
  
  
  RESULTS
  64 patients, 25 submitted to hip replacement surgery due to fragility fracture and 39 due to osteoarthritis, were evaluated. Bone OC/collagen expression (OC/COL1A1) ratio was significantly lower in hip fracture compared to osteoarthritis patients (p<0.017) adjusted for age, gender and body mass index. Moreover, OC/COL1A1 expression ratio was associated with the hip fracture event (OR ~0; p=0.003) independently of the group assigned, or the clinical characteristics. Apoε4 isoform was more frequent in the hip fracture group (p=0.029). ucOC levels were higher in the fracture group although not significantly (p=0.058). No differences were found regarding total OC (p=0.602), apoE (p=0.467) and Vitamin K (p=0.371). In hip fracture patients, multivariate analysis, adjusted for clinical characteristics, serum factors related to OC metabolism and gene expression of bone matrix proteins showed that low OC/COL1A1 expression ratio was significantly associated with worse trabecular strength (β=0.607; p=0.013) and stiffness (β=0.693; p=0.003). No association was found between ucOC and bone mechanics. Moreover, in osteoarthritis patients, the multivariate analysis revealed that serum total OC was negatively associated with strength (β=-0.411; p=0.030) and stiffness (β=-0.487; p=0.009).
  
  
  CONCLUSIONS
  We demonstrated that low bone OC/COL1A1 expression ratio was an independent predictor of worse trabecular mechanical behavior and of the hip fracture event. These findings suggest that in hip fracture patients the imbalance of bone OC/COL1A1 expression ratio reflects disturbances in osteoblast activity leading to bone fragility.
authors.affiliation: Rheumatology Research Unit, Instituto de Medicina Molecular, Lisbon, Portugal. anamfrodrigues@gmail.com
authors.forename: Ana M
authors.initials: AM
authors.lastname: Rodrigues
authors.forename: Joana
authors.initials: J
authors.lastname: Caetano-Lopes
authors.forename: Ana C
authors.initials: AC
authors.lastname: Vale
authors.forename: Bruno
authors.initials: B
authors.lastname: Vidal
authors.forename: Ana
authors.initials: A
authors.lastname: Lopes
authors.forename: Inês
authors.initials: I
authors.lastname: Aleixo
authors.forename: Joaquim
authors.initials: J
authors.lastname: Polido-Pereira
authors.forename: Alexandre
authors.initials: A
authors.lastname: Sepriano
authors.forename: Inês P
authors.initials: IP
authors.lastname: Perpétuo
authors.forename: Jacinto
authors.initials: J
authors.lastname: Monteiro
authors.forename: Maria F
authors.initials: MF
authors.lastname: Vaz
authors.forename: João E
authors.initials: JE
authors.lastname: Fonseca
authors.forename: Helena
authors.initials: H
authors.lastname: Canhão
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism*; D016022:Case-Control Studies; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006620:Hip Fractures / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism; D015675:Osteocalcin / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D024042:Collagen Type I; D015675:Osteocalcin