title: Lubricin restoration in a mouse model of congenital deficiency.
abstract: OBJECTIVE
  Congenital deficiency of the principal boundary lubricant in cartilage (i.e., lubricin, encoded by the gene PRG4) increases joint friction and causes progressive joint failure. This study was undertaken to determine whether restoring lubricin expression in a mouse model would prevent, delay, or reverse the disease process caused by congenital deficiency.
  
  
  METHODS
  Using genetically engineered lubricin-deficient mice, we restored gene function before conception or at ages 3 weeks, 2 months, or 6 months after birth. The effect of restoring gene function (i.e., expression of lubricin) on the tibiofemoral patellar joints of mice was evaluated histologically and by ex vivo biomechanical testing.
  
  
  RESULTS
  Restoring gene function in mice prior to conception prevented joint disease. In 3-week-old mice, restoring gene function improved, but did not normalize, histologic features of the articular cartilage and whole-joint friction. In addition, cyclic loading of the joints produced fewer activated caspase 3-containing chondrocytes when lubricin expression was restored, as compared to that in littermate mice whose gene function was not restored (nonrestored controls). Restoration of lubricin expression in 2-month-old or 6-month-old mice had no beneficial effect on histopathologic cartilage damage, extent of whole-joint friction, or activation of caspase 3 when compared to nonrestored controls.
  
  
  CONCLUSIONS
  When boundary lubrication is congenitally deficient and cartilage becomes damaged, the window of opportunity for restoring lubrication and slowing disease progression is limited.
authors.affiliation: Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Adele
authors.initials: A
authors.lastname: Hill
authors.affiliation: Alpert Medical School of Brown University and Rhode Island Hospital, Providence.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Waller
authors.affiliation: Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Allen
authors.affiliation: Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Patrick
authors.initials: P
authors.lastname: Smits
authors.affiliation: Alpert Medical School of Brown University and Rhode Island Hospital, Providence.
authors.forename: Ling X
authors.initials: LX
authors.lastname: Zhang
authors.affiliation: Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Ugur M
authors.initials: UM
authors.lastname: Ayturk
authors.affiliation: Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Steven
authors.initials: S
authors.lastname: Hann
authors.affiliation: Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Samantha G
authors.initials: SG
authors.lastname: Lessard
authors.affiliation: Boston Children's Hospital, Boston, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: Zurakowski
authors.affiliation: Howard Hughes Medical Institute, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Warman
authors.affiliation: Rhode Island Hospital, Alpert Medical School of Brown University, and Brown University School of Engineering, Providence, Rhode Island.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Jay
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D015316:Genetic Therapy; D007719:Knee Joint / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011509:Proteoglycans / Q000235:genetics* / Q000378:metabolism; D016059:Range of Motion, Articular; D000099158:Proteoglycan 4
chemical_list: D011509:Proteoglycans; C498837:Prg4 protein, mouse; D000099158:Proteoglycan 4