Abstract
Osteoarthritis (OA) is a progressive degenerative disease of the joints caused in part by a change in the phenotype of resident chondrocytes within affected joints. This altered phenotype, often termed proinflammatory or procatabolic, features enhanced production of endoproteinases and matrix metallo-proteinases (MMPs) as well as secretion of endogenous inflammatory mediators. Degradation and reduced retention of the proteoglycan aggrecan is an early event in OA. Enhanced turnover of hyaluronan (HA) is closely associated with changes in aggrecan. Here, to determine whether experimentally increased HA production promotes aggrecan retention and generates a positive feedback response, we overexpressed HA synthase-2 (HAS2) in chondrocytes via an inducible adenovirus construct (HA synthase-2 viral overexpression; HAS2-OE). HAS2-OE incrementally increased high-molecular-mass HA >100-fold within the cell-associated and growth medium pools. More importantly, our results indicated that the HAS2-OE expression system inhibits MMP3, MMP13, and other markers of the procatabolic phenotype (such as TNF-stimulated gene 6 protein (TSG6)) and also enhances aggrecan retention. These markers were inhibited in OA-associated chondrocytes and in chondrocytes activated by interleukin-1β (IL1β), but also chondrocytes activated by lipopolysaccharide (LPS), tumor necrosis factor α (TNFα), or HA oligosaccharides. However, the enhanced extracellular HA resulting from HAS2-OE did not reduce the procatabolic phenotype of neighboring nontransduced chondrocytes as we had expected. Rather, HA-mediated inhibition of the phenotype occurred only in transduced cells. In addition, high HA biosynthesis rates, especially in transduced procatabolic chondrocytes, resulted in marked changes in chondrocyte dependence on glycolysis versus oxidative phosphorylation for their metabolic energy needs.
Highlights
Osteoarthritis (OA) is a progressive degenerative disease of the joints caused in part by a change in the phenotype of resident chondrocytes within affected joints
This occurs even though IL1 enhances the synthesis of endogenous chondrocyte HA synthase-2 (HAS2) [8]
We subsequently determined that HA and bound aggrecan G1 domains were rapidly internalized by CD44 after IL1 activation, in close coordination with the ADAMTS/matrix metallo-proteinases (MMPs)-mediated cleavage and release of degraded aggrecan monomers [4, 32, 33]
Summary
The question raised is whether forced repair of the chondrocyte pericellular matrix chondrocytes reverses or diminishes the procatabolic phenotype. Given that the chondrocytes have a very low cell proliferation rate, we have observed continuous viral transduction extending from weeks to months. With these tools, we sought to determine the effects of enhancing HA production by the chondrocytes at the local level, with variable HA synthesis allowed to occur in parallel with experimental challenge by cytokines or other pro-inflammatory mediators. We sought to determine the effects of enhancing HA production by the chondrocytes at the local level, with variable HA synthesis allowed to occur in parallel with experimental challenge by cytokines or other pro-inflammatory mediators Such data will address whether chondrocytes can sense that HA repair has occurred and signal chondrocytes to return to quiescent homeostasis
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