Anti-senescence and Anti-inflammatory Effects of the C-terminal Moiety of PTHrP Peptides in OA Osteoblasts

• Published in: The journals of gerontology. Series A, Biological sciences and medical sciences Vol. 72; no. 5; pp. 624 - 631
• Main Authors: Platas, Julia, Guillén, Maria Isabel, Gomar, Francisco, Castejón, Miguel Angel, Esbrit, Pedro, Alcaraz, Maria José
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01-05-2017
• Subjects: Activator protein 1; Aged; Anti-inflammatory agents; Arthritis; Bone turnover; Caveolin; Caveolin-1; Cells; Cells, Cultured; Cellular Senescence - physiology; Cyclooxygenase-2; Dinoprostone - metabolism; Effects; Female; Fluorescent Antibody Technique; Geriatrics; Gerontology; GTP-binding protein; Humans; Inflammation; Inflammation Mediators - pharmacology; Interleukin 6; Interleukin-1beta - pharmacology; Interleukin-6 - metabolism; Male; Metabolism; NF-κB protein; Older people; Osteoarthritis; Osteoarthritis - metabolism; Osteoarthritis - prevention & control; Osteoblasts; Osteoblasts - cytology; Oxygenase; p53 Protein; Parathyroid; Parathyroid hormone; Parathyroid hormone-related protein; Parathyroid Hormone-Related Protein - pharmacology; Peptide Fragments - pharmacology; Peptides; Physical disabilities; Prostaglandin E2; Prostaglandin endoperoxide synthase; Real-Time Polymerase Chain Reaction; Senescence; Subchondral bone; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; β-Galactosidase; Senescence; Parathyroid hormone; derived peptides; Inflammation; Osteoarthritis; Osteoblasts; related protein (PTHrP)
• ISSN: 1079-5006; 1758-535X
• DOI: 10.1093/gerona/glw100

Osteoarthritis (OA) is characterized by degenerative changes in the whole joint leading to physical disability in the elderly population. This condition is associated with altered bone metabolism in subchondral areas suggesting that therapeutic strategies aimed at modifying bone cell metabolism may be of interest. We have investigated the effects of several parathyroid hormone-related protein (PTHrP)-derived peptides (1-37): (N-terminal), (107-111) and (107-139) (C-terminal) on senescence features induced by inflammatory stress in human OA osteoblasts. Incubation of these primary cells with interleukin(IL)-1β led to an increased expression of senescence markers senescence-associated-β-galactosidase activity, γH2AX foci, p16, p21, p53, and caveolin-1. PTHrP (107-111) and PTHrP (107-139) significantly reduced all these parameters. Both peptides decreased the production of IL-6 and prostaglandin E2 which was the consequence of cyclo-oxygenase-2 downregulation. PTHrP (107-139) also reduced tumor necrosis factor-α release. These anti-inflammatory effects would be related to the reduction of nuclear factor-κB activation by both peptides and activator protein-1 by PTHrP (107-139). The three PTHrP peptides favored osteoblastic function although the C-terminal domain of PTHrP was more efficient than its N-terminal domain. Our data support an anti-senescence and anti-inflammatory role for the C-terminal moiety of PTHrP with potential applications in chronic inflammatory conditions such as OA.