title: Heterozygosity for an inactivating mutation in low-density lipoprotein-related receptor 6 (Lrp6) increases osteoarthritis severity in mice after ligament and meniscus injury.
abstract: OBJECTIVE
  Wnt/β-catenin signaling plays an integral and complex role in cartilage development and maintenance. β-catenin signaling has been linked to osteoarthritis (OA), but the role of Lrp6-mediated Wnt/β-catenin signaling during OA remains unexplored. Mutations in the Wnt/β-catenin co-receptors LRP5 and LRP6 (low-density lipoprotein-related receptors 5 and 6) result in skeletal abnormalities, which tend to be more severe in Lrp6 mutant mice. We examined OA development, chondrocyte and osteoblast behavior, and β-catenin signaling after ligament and meniscus damage in mice with global heterozygous deletion of Lrp6.
  
  
  METHODS
  Ligament and meniscus damage was surgically induced in Lrp6(+/-) and wild-type (WT) mice, and evidence of joint disease was assessed by Microcomputed tomography (micro-CT) and histology. Wnt/β-catenin signaling, proliferation, apoptosis, chondrogenesis, osteogenesis, and catabolic enzyme activity were measured.
  
  
  RESULTS
  Relative to WT mice, Lrp6(+/-) mice had lower nuclear β-catenin signaling within articular cartilage. After surgery, osteophytes and reduced articular cartilage were apparent in WT mice, but more severe in Lrp6(+/-) animals. Impairments to trabecular bone geometry occurred for WT and Lrp6(+/-) mice after surgery. Relative to WT mice, Lrp6(+/-) mice had reduced trabecular BMD and thickness, and Cyclin D1 and Lrp6 gene expression after surgery. There was an increase in apoptotic cells and serum matrix metalloproteinase-9 (MMP9) for Lrp6(+/-) mice after surgery, but no differences in cell proliferation occurred.
  
  
  CONCLUSIONS
  Heterozygous loss-of-function mutation in Lrp6 leads to less β-catenin signaling within articular cartilage and to increased degenerative joint disease after ligament and meniscus injury. Modulation of Lrp6 function could attenuate joint disease after damage to ligaments and the meniscus.
authors.affiliation: Center for Skeletal Disease Research, Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA. Electronic address: danese.joiner@vai.org.
authors.forename: D M
authors.initials: DM
authors.lastname: Joiner
authors.forename: K D
authors.initials: KD
authors.lastname: Less
authors.forename: E M
authors.initials: EM
authors.lastname: Van Wieren
authors.forename: D
authors.initials: D
authors.lastname: Hess
authors.forename: B O
authors.initials: BO
authors.lastname: Williams
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism; D006579:Heterozygote; D008023:Ligaments, Articular / Q000293:injuries; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013977:Tibia / Q000473:pathology; D000070600:Tibial Meniscus Injuries; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D051176:beta Catenin
keywords: Ligament; Low-density lipoprotein-related receptor 6 (LRP6); Meniscus; Osteoarthritis; Wnt/β-catenin signaling