Prevention of cartilage degeneration in a rat model of osteoarthritis by intraarticular treatment with recombinant lubricin

Abstract

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.Conclusion. Our findings demonstrate the potential use of recombinant lubricin molecules in novel biotherapeutic approaches to the treatment of OA and associated cartilage abnormalities.Osteoarthritis (OA) severely restricts the daily activities, mobility, and overall quality of life of millions of patients worldwide, imposing a high societal burden that reflects the current lack of effective medical therapies. OA is characterized by escalated degeneration and loss of articular cartilage, the specialized connective tissue covering the ends of interfacing bones within joints. To help withstand formidable biomechanical forces and loads, articular cartilage surfaces possess an inherently low coefficient of friction, which is facilitated in part by localization of the boundary lubricant lubricin (1). Lubricin was originally identified as a lubricating glycoprotein present in synovial fluid (2), and it is now recognized to have a major protective role in preventing cartilage wear and synovial cell adhesion and proliferation (3). Lubricin is encoded by the PRG4 gene, and PRG4-nullifying mutations can cause OA-like symptoms in mice and humans (3,4). Lubricin synthesis/localization (and therefore function) is also down-regulated in sheep (5), guinea pig (6), and rat (7)

Role of lubricin and boundary lubrication in the prevention of chondrocyte apoptosis

“…Lubricin levels in SF decrease after anterior cruciate ligament injury and can take up to a year to return to baseline values (40). Several studies have demonstrated a disease-modifying effect for the intraarticular injection of native or recombinantly expressed lubricin in rodent models of posttraumatic OA (28,29,41,42). Our data indicate that lubricin supplementation likely protects damaged joints by preserving boundary lubrication, thereby protecting articular chondrocytes from apoptosis caused by excessive deformation and shear stress.…”

LXR modulation blocks prostaglandin E 2 production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model

“…After 13 weeks of treatment, animals were killed and joints were harvested. OA pathology scores were assessed by histologic analysis as described previously (32).…”

Development of a Cartilage Shear-Damage Model to Investigate the Impact of Surface Injury on Chondrocytes and Extracellular Matrix Wear

“…For the latter, the loss starts a cascade of effects including increased friction, increased shear stress across the surface, and ultimately increased cartilage wear and joint degradation. 16 Furthermore, shear stress has been documented with in vitro studies as a negative factor in cartilage failure as a response to injury and extracellular matrix wear. 17,18 Development of a superficial zone damage model through excessive shear would highlight the role of the superficial zone in the progression from healthy cartilage to PTOA.…”