Abstract
An activation of osteoclasts and subchondral bone remodeling is a major histologic feature of early-stage osteoarthritis (OA), which can be accompanied by an increase of calcium (Ca) and phosphate (Pi) level in the subchondral milieu. Considering articular cartilage gets most of nutrition from subchondral bone by diffusion, these micro-environmental changes in subchondral bone can affect the physiology of articular chondrocytes. Here, we have shown that Ca is increased and co-localized with Pi in articular cartilage of early-stage OA. The Ca-Pi complex increased the production of MMP-3 and MMP-13 in the hypertrophic chondrocytes, which was dependent on nuclear factor-kappa B (NF-kB), p38 and extracellular signal-regulated kinase (Erk) 1/2 mitogen-activated protein (MAP) kinase and Signal transducer and activator of transcription 3 (STAT3) signaling. The Ca-Pi complexes increased the expression of endocytosis markers, and the inhibition of the formation of the Ca-Pi complex ameliorated the Ca-Pi complex-mediated increases of MMPs expression in hypertrophic chondrocytes. Our data provide insight regarding the Ca-Pi complex as a potential catabolic mediator in the subchondral milieu and support the pathogenic role of subchondral bone in the early stages of cartilage degeneration.
Highlights
Osteoarthritis (OA) is the most common type of degenerative joint arthritis and is characterized by cartilage loss and osteophyte formation[1]
We analyzed the Ca-Pi complex-mediated global protease expression in hypertrophic chondrocytes, which revealed a significant increase in matrix metalloprotease (MMP)-3 and MMP-13 expression that was dependent on nuclear factor-kappa B (NF-kB), p38 and Erk1/2 mitogen-activated protein (MAP) kinase signaling
Evidence of increased subchondral bone remodeling in early OA prompted us to investigate whether Ca and Pi are increased in articular cartilage in OA16, which were quantified using ToF-SIMS analyses
Summary
Osteoarthritis (OA) is the most common type of degenerative joint arthritis and is characterized by cartilage loss and osteophyte formation[1]. Persistent mechanical stress induces a hypertrophic change in articular chondrocytes and the production of cartilage matrix-degrading proteases, such as matrix metalloprotease (MMP)-3, MMP-13, disintegrin and metalloproteinase with thrombospondin motifs 5 (Adamts[5]) Due to these changes, a central area in the cartilage undergoes cartilage loss, and the peripheral cartilage with a good blood supply from the synovium forms osteophytes through endochondral bone formation[2,3]. Several studies investigating the pathogenesis of OA converge on the molecular cascades of producing cartilage matrix degrading proteases, such as MMP-13 and Adamts[54] In the producing these proteases, a lot of signaling mechanisms and transcription factors have been known to be involved as major upstream including nuclear factor-kappa B (NF-kB), mitogen-activated protein (MAP) kinases, hypoxia-induced factor 2 alpha (Hif-2α), and runt-related transcription factor 2 (Runx2)[4,5]. Our results provide insights into the mechanisms by which the changes in subchondral bone can affect articular cartilage degradation
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