title: Intra-articular Recombinant Human Proteoglycan 4 Mitigates Cartilage Damage After Destabilization of the Medial Meniscus in the Yucatan Minipig.
abstract: BACKGROUND
  Lubricin, or proteoglycan 4 (PRG4), is a glycoprotein responsible for joint boundary lubrication. PRG4 has been shown previously to be down-regulated after traumatic joint injury such as a meniscal tear. Preliminary evidence suggests that intra-articular injection of PRG4 after injury will reduce cartilage damage in rat models of surgically induced posttraumatic osteoarthritis.
  
  
  OBJECTIVE
  To determine the efficacy of intra-articular injection of full-length recombinant human lubricin (rhPRG4) for reducing cartilage damage after medial meniscal destabilization (DMM) in a preclinical large animal model.
  
  
  METHODS
  Controlled laboratory study.
  
  
  METHODS
  Unilateral DMM was performed in 29 Yucatan minipigs. One week after DMM, animals received 3 weekly intra-articular injections (3 mL per injection): (1) rhPRG4 (1.3 mg/mL; n = 10); (2) rhPRG4+hyaluronan (1.3 mg/mL rhPRG4 and 3 mg/mL hyaluronan [~950 kDA]; n = 10); and (3) phosphate-buffered saline (PBS; n = 9). Hindlimbs were harvested 26 weeks after surgery. Cartilage integrity was evaluated by use of macroscopic (India ink) and microscopic (safranin O-fast green and hematoxylin and eosin) scoring systems. Secondary outcomes evaluated via enzyme-linked immunosorbent assay (ELISA) included PRG4 levels in synovial fluid, carboxy-terminal telepeptide of type II collagen (CTX-II) concentrations in urine and serum, and interleukin 1β (IL-1β) levels in synovial fluid and serum.
  
  
  RESULTS
  The rhPRG4 group had significantly less macroscopic cartilage damage in the medial tibial plateau compared with the PBS group ( P = .002). No difference was found between the rhPRG4+hyaluronan and PBS groups ( P = .23). However, no differences in microscopic damage scores were observed between the 3 groups ( P = .70). PRG4 production was elevated in the rhPRG4 group synovial fluid compared with the PBS group ( P = .033). The rhPRG4 group presented significantly lower urinary CTX-II levels, but not serum levels, when compared with the PBS ( P = .013) and rhPRG4+hyaluronan ( P = .011) groups. In serum and synovial fluid, both rhPRG4 ( P = .006; P = .017) and rhPRG4+hyaluronan groups ( P = .009; P = .03) presented decreased IL-1β levels.
  
  
  CONCLUSIONS
  All groups exhibited significant cartilage degeneration after DMM surgery. However, animals treated with rhPRG4 had the least amount of cartilage damage and less inflammation, providing evidence that intra-articular injections of rhPRG4 may slow the progression of posttraumatic osteoarthritis.
  
  
  CONCLUSIONS
  Patients with meniscal trauma are at high risk for posttraumatic osteoarthritis. This study demonstrates that an intra-articular injection regimen of rhPRG4 may attenuate cartilage damage after meniscal injury.
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Waller
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island, USA.
authors.forename: Kaitlyn E
authors.initials: KE
authors.lastname: Chin
authors.affiliation: Department of Emergency Medicine, Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island, USA.|School of Engineering, Brown University, Providence, Rhode Island, USA.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Jay
authors.affiliation: Department of Emergency Medicine, Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island, USA.
authors.forename: Ling X
authors.initials: LX
authors.lastname: Zhang
authors.affiliation: Department of Occupational and Environmental Medicine, Harvard School of Public Health, Boston, Massachusetts, USA.|Department of Orthopedic Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Teeple
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: McAllister
authors.affiliation: Department of Medical Biostatistics, University of Vermont, Burlington, Vermont, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Badger
authors.affiliation: Faculty of Kinesiology & Schulich School of Engineering, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Tannin A
authors.initials: TA
authors.lastname: Schmidt
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island, USA.|School of Engineering, Brown University, Providence, Rhode Island, USA.
authors.forename: Braden C
authors.initials: BC
authors.lastname: Fleming
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000293:injuries*; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology; D007270:Injections, Intra-Articular; D008297:Male; D011509:Proteoglycans / Q000494:pharmacology*; D011897:Random Allocation; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine; D013556:Swine, Miniature; D000070600:Tibial Meniscus Injuries / Q000378:metabolism / Q000628:therapy*; D000099158:Proteoglycan 4
chemical_list: D006820:Hyaluronic Acid; D011509:Proteoglycans; D011994:Recombinant Proteins; C419197:PRG4 protein, human; D000099158:Proteoglycan 4
keywords: PRG4; hyaluronan; inflammation; lubricin; meniscus; osteoarthritis