title: Deficiency of hyaluronan synthase 1 (Has1) results in chronic joint inflammation and widespread intra-articular fibrosis in a murine model of knee joint cartilage damage.
abstract: OBJECTIVE
  Articular cartilage defects commonly result from traumatic injury and predispose to degenerative joint diseases. To test the hypothesis that aberrant healing responses and chronic inflammation lead to osteoarthritis (OA), we examined spatiotemporal changes in joint tissues after cartilage injury in murine knees. Since intra-articular injection of hyaluronan (HA) can attenuate injury-induced osteoarthritis in wild-type (WT) mice, we investigated a role for HA in the response to cartilage injury in mice lacking HA synthase 1 (Has1(-/-)).
  
  
  METHODS
  Femoral groove cartilage of WT and Has1(-/-) mice was debrided to generate a non-bleeding wound. Macroscopic imaging, histology, and gene expression were used to evaluate naïve, sham-operated, and injured joints.
  
  
  RESULTS
  Acute responses (1-2 weeks) in injured joints from WT mice included synovial hyperplasia with HA deposition and joint-wide increases in expression of genes associated with inflammation, fibrosis, and extracellular matrix (ECM) production. By 4 weeks, some resurfacing of damaged cartilage occurred, and early cell responses were normalized. Cartilage damage in Has1(-/-) mice also induced early responses; however, at 4 weeks, inflammation and fibrosis genes remained elevated with widespread cartilage degeneration and fibrotic scarring in the synovium and joint capsule.
  
  
  CONCLUSIONS
  We conclude that the ineffective repair of injured cartilage in Has1(-/-) joints can be at least partly explained by the markedly enhanced expression of particular genes in pathways linked to ECM turnover, IL-17/IL-6 cytokine signaling, and apoptosis. Notably, Has1 ablation does not alter gross HA content in the ECM, suggesting that HAS1 has a unique function in the metabolism of inflammatory HA matrices.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA. Electronic address: deva_chan@rush.edu.
authors.forename: D D
authors.initials: DD
authors.lastname: Chan
authors.affiliation: Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: wenfeng_xiao@163.com.
authors.forename: W F
authors.initials: WF
authors.lastname: Xiao
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA. Electronic address: jun_li@rush.edu.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: delamoc@ccf.org.
authors.forename: C A
authors.initials: CA
authors.lastname: de la Motte
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA; Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, USA. Electronic address: jsandy44@gmail.com.
authors.forename: J D
authors.initials: JD
authors.lastname: Sandy
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA; Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA. Electronic address: anna_plaas@rush.edu.
authors.forename: A
authors.initials: A
authors.lastname: Plaas
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000201:enzymology / Q000293:injuries / Q000473:pathology*; D002908:Chronic Disease; D004195:Disease Models, Animal; D005355:Fibrosis / Q000201:enzymology / Q000473:pathology; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D000076002:Hyaluronan Synthases; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007719:Knee Joint / Q000201:enzymology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020370:Osteoarthritis, Knee / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*
chemical_list: D012313:RNA; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases
keywords: Cartilage; Fibrotic scar; Hyaluronan synthases; Inflammation; Injury; Synovium