title: Upregulation of inflammatory genes and downregulation of sclerostin gene expression are key elements in the early phase of fragility fracture healing.
abstract: BACKGROUND
  Fracture healing is orchestrated by a specific set of events that culminates in the repair of bone and reachievement of its biomechanical properties. The aim of our work was to study the sequence of gene expression events involved in inflammation and bone remodeling occurring in the early phases of callus formation in osteoporotic patients.
  
  
  RESULTS
  Fifty-six patients submitted to hip replacement surgery after a low-energy hip fracture were enrolled in this study. The patients were grouped according to the time interval between fracture and surgery: bone collected within 3 days after fracture (n = 13); between the 4(th) and 7(th) day (n = 33); and after one week from the fracture (n = 10). Inflammation- and bone metabolism-related genes were assessed at the fracture site. The expression of pro-inflammatory cytokines was increased in the first days after fracture. The genes responsible for bone formation and resorption were upregulated one week after fracture. The increase in RANKL expression occurred just before that, between the 4(th)-7(th) days after fracture. Sclerostin expression diminished during the first days after fracture.
  
  
  CONCLUSIONS
  The expression of inflammation-related genes, especially IL-6, is highest at the very first days after fracture but from day 4 onwards there is a shift towards bone remodeling genes, suggesting that the inflammatory phase triggers bone healing. We propose that an initial inflammatory stimulus and a decrease in sclerostin-related effects are the key components in fracture healing. In osteoporotic patients, cellular machinery seems to adequately react to the inflammatory stimulus, therefore local promotion of these events might constitute a promising medical intervention to accelerate fracture healing.
authors.affiliation: Rheumatology Research Unit, Faculdade de Medicina da Universidade de Lisboa, Instituto de Medicina Molecular, Lisbon, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Caetano-Lopes
authors.forename: Ana
authors.initials: A
authors.lastname: Lopes
authors.forename: Ana
authors.initials: A
authors.lastname: Rodrigues
authors.forename: Diana
authors.initials: D
authors.lastname: Fernandes
authors.forename: Inês P
authors.initials: IP
authors.lastname: Perpétuo
authors.forename: Teresa
authors.initials: T
authors.lastname: Monjardino
authors.forename: Raquel
authors.initials: R
authors.lastname: Lucas
authors.forename: Jacinto
authors.initials: J
authors.lastname: Monteiro
authors.forename: Yrjö T
authors.initials: YT
authors.lastname: Konttinen
authors.forename: Helena
authors.initials: H
authors.lastname: Canhão
authors.forename: João E
authors.initials: JE
authors.lastname: Fonseca
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000369:Aged, 80 and over; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D016723:Bone Remodeling / Q000235:genetics; D002146:Bony Callus / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D017102:Fracture Healing / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics*; D006620:Hip Fractures / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D010011:Osteocytes / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin / Q000235:genetics; D053245:RANK Ligand / Q000235:genetics; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C422903:SOST protein, human