Prevention of cartilage degeneration in a rat model of osteoarthritis by intraarticular treatment with recombinant lubricin.
OBJECTIVE
Lubricin, also referred to as superficial zone protein and PRG4, is a synovial glycoprotein that supplies a friction-resistant, antiadhesive coating to the surfaces of articular cartilage, thereby protecting against arthritis-associated tissue wear and degradation. This study was undertaken to generate and characterize a novel recombinant lubricin protein construct, LUB:1, and to evaluate its therapeutic efficacy following intraarticular delivery in a rat model of osteoarthritis (OA).


METHODS
Binding and localization of LUB:1 to cartilage surfaces was assessed by immunohistochemistry. The cartilage-lubricating properties of LUB:1 were determined using a custom friction testing apparatus. A cell-binding assay was performed to quantify the ability of LUB:1 to prevent cell adhesion. Efficacy studies were conducted in a rat meniscal tear model of OA. One week after the surgical induction of OA, LUB:1 or phosphate buffered saline vehicle was administered by intraarticular injection for 4 weeks, with dosing intervals of either once per week or 3 times per week. OA pathology scores were determined by histologic analysis.


RESULTS
LUB:1 was shown to bind effectively to cartilage surfaces, and facilitated both cartilage boundary lubrication and inhibition of synovial cell adhesion. Treatment of rat knee joints with LUB:1 resulted in significant disease-modifying, chondroprotective effects during the progression of OA, by markedly reducing cartilage degeneration and structural damage.


CONCLUSIONS
Our findings demonstrate the potential use of recombinant lubricin molecules in novel biotherapeutic approaches to the treatment of OA and associated cartilage abnormalities.
Flannery
Carl R
CR
Wyeth Research, Cambridge, Massachusetts, USA. cflannery@wyeth.com
Zollner
Richard
R
Corcoran
Chris
C
Jones
Aled R
AR
Root
Adam
A
Rivera-Bermúdez
Moisés A
MA
Blanchet
Tracey
T
Gleghorn
Jason P
JP
Bonassar
Lawrence J
LJ
Bendele
Alison M
AM
Morris
Elisabeth A
EA
Glasson
Sonya S
SS
D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000293:injuries / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D006023:Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007270:Injections, Intra-Articular; D008297:Male; D010003:Osteoarthritis / Q000473:pathology* / Q000517:prevention & control*; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013583:Synovial Membrane / Q000187:drug effects / Q000473:pathology; D016896:Treatment Outcome; D000099158:Proteoglycan 4
D006023:Glycoproteins; D011994:Recombinant Proteins; D000099158:Proteoglycan 4