Abstract
Cartilage and the bordering subchondral bone form a functionally active regulatory interface with a prominent role in osteoarthritis pathways. The Wnt and the OPG-RANKL-RANK signaling systems, as key mediators, interact in subchondral bone remodeling. Osteoarthritic osteoblasts polarize into two distinct phenotypes: a low secretory and an activated, pro-inflammatory and anti-resorptive subclass producing high quantities of IL-6, PGE2, and osteoprotegerin, but low levels of RANKL, thus acting as putative effectors of subchondral bone sclerosis. Wnt agonists, Wnt5a, Wisp-1 initiate excessive bone remodeling, while Wnt3a and 5a simultaneously cause loss of proteoglycans and phenotype shift in chondrocytes, with decreased expression of COL2A, aggrecan, and Sox-9. Sclerostin, a Wnt antagonist possesses a protective effect for the cartilage, while DKK-1 inhibits VEGF, suspending neoangiogenesis in the subchondral bone. Experimental conditions mimicking abnormal mechanical load, the pro-inflammatory milieu, but also a decreased OPG/RANKL ratio in the cartilage, trigger chondrocyte apoptosis and loss of the matrix via degradative matrix metalloproteinases, like MMP-13 or MMP-9. Hypoxia, an important cofactor exerts a dual role, promoting matrix synthesis via HIF-1α, a Wnt silencer, but turning on HIF-2α that enhances VEGF and MMP-13, along with aberrant collagen expression and extracellular matrix deterioration in the presence of pro-inflammatory cytokines.
Highlights
Osteoarthritis is a complex, chronic disease that affects primarily the weight-bearing joints of humans and other mammals
Bouaziz et al [162] reported that hypoxia inducible factor-1α (HIF-1α) is down-regulated in osteoarthritic mice, and chondrocytespecific deletion of HIF-1α enhances the destruction of cartilage through inducing matrix metalloproteinases (MMPs)-13 activation
Osteoarthritic osteoblasts have two different phenotypes: low-synthesizer cells produce little IL-6, PGE2, and OPG, whereas high-synthesizers secrete more of these mediators but low amounts of receptor activator of nuclear kappa B ligand (RANKL)
Summary
Osteoarthritis is a complex, chronic disease that affects primarily the weight-bearing joints of humans and other mammals. During progression of the disease, all compartments of the joints undergo structural, functional and metabolic changes that involve cellular elements as well as components of the extracellular matrix. Chondrocytes, the only cells of the cartilage, are responsible for the biochemical turnover, synthesis, and secretion of the extracellular matrix component; the cells differ in shape and size in various areas of cartilage, but all forms contain cellular organelles required for matrix synthesis. Chondrocytes adapt their metabolism to physicochemical changes of the microenvironment as mechanical and osmotic sensors [3,4]. Besides monocytes/macrophages infiltrating the synovial membrane, an important source of the pro-inflammatory mediators released to the cartilage, might be the subchondral bone, and, especially, subchondral osteoblasts
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