Session Type: Abstract Submissions (ACR)
In osteoarthritis (OA), there is an abnormal remodeling process in subchondral bone associated with an altered osteoblast metabolism. Inflammatory mediators participate in bone remodeling and cartilage degradation during OA progression. Parathyroid hormone (PTH) and its bone counterpart, PTH-related protein (PTHrP), increase bone turnover through interaction of their N-terminal domain with the PTH type 1 receptor in osteoblasts. PTHrP peptides may be a novel approach to treat bone metabolic alterations. The aim of this study was to investigate the effects of different PTHrP peptides, PTHrP (1-37), and the PTH-unrelated peptides, PTHrP (107-139) and PTHrP (107-111) (osteostatin), on osteoblast senescence and the production of inflammatory mediators and degradative enzymes in osteoarthritic human osteoblasts stimulated with interleukin-1β (IL-1β).
Osteoblasts were obtained from 8 patients undergoing total knee joint replacement. Subchondral bone tissue obtained from tibial plateau was minced into small portions and digested with collagenase under agitation. Collected tissue was seeded in osteogenic medium to obtain osteoblastic cells according to a standard procedure. At first passage, osteoblastic cells were treated with PTHrP (1-37), PTHrP (107-139) and osteostatin (each at 100 nM) with or without IL-1β (10 ng/ml) for 1, 3 and 6 days. Senescence-associated β-galactosidase activity (SA-β-Gal) was assessed by cytochemistry. mRNA expression of matrix metalloproteinases (MMPs) and senescence markers was determined by qPCR. Prostaglandin E2 (PGE2) was measured by RIA, pro-inflammatory cytokines by ELISA, and cyclooxygenase-2 (COX-2) expression was determined by immunocytochemistry.
IL-1β increased senescence features and the secretion of inflammatory mediators in osteoarthritic osteoblasts. Increased production of cytokines, MMPs and PGE2 may contribute to bone sclerosis and degradative processes in the joint. The three PTHrP peptides tested significantly down-regulated SA-β-Gal and the expression of caveolin-1, p21, p53, MMP-1 and MMP-3. In addition, these peptides reduced the release of tumor necrosis factor-α into the culture medium. PGE2 production was significantly decreased by PTHrP (1-37) on days 1, 3 and 6, and also by each C-terminal PTHrP peptide on day 6. This effect on PGE2 was dependent on the downregulation of IL-1β-induced COX-2 overexpression.
These findings show that both N- and C-terminal PTHrP peptides counteract the effects of IL-1β on the induction of cell senescence and the production of inflammatory and degradative mediators in osteoarthritic human osteoblasts, suggesting a beneficial effect of these peptides in osteoarthritic subchondral bone.
M. I. Guillén,
M. J. Alcaraz,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/regulation-of-senescence-and-inflammatory-mediators-by-n-and-c-terminal-parathyroid-hormone-related-protein-in-osteoarthritic-human-osteoblasts/