Anti-senescence and Anti-inflammatory Effects of the C-terminal Moiety of PTHrP Peptides in OA Osteoblasts.
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.
Department of Pharmacology and IDM, University of Valencia, Valencia, Spain.|Cooperative Research Thematic Network on Aging and Frailty (RETICEF), ISCIII, Madrid, Spain.
Julia
J
Platas
Department of Pharmacology and IDM, University of Valencia, Valencia, Spain.|Cooperative Research Thematic Network on Aging and Frailty (RETICEF), ISCIII, Madrid, Spain.|Department of Pharmacy, Cardenal Herrera-CEU University, Valencia, Spain.
Maria Isabel
MI
Guillén
Cooperative Research Thematic Network on Aging and Frailty (RETICEF), ISCIII, Madrid, Spain.|Department of Surgery, Faculty of Medicine, University of Valencia, Valencia, Spain.
Francisco
F
Gomar
Department of Orthopaedic Surgery and Traumatology, De la Ribera University Hospital, Valencia, Spain.
Miguel Angel
MA
Castejón
Cooperative Research Thematic Network on Aging and Frailty (RETICEF), ISCIII, Madrid, Spain.|Joint and Bone Research Unit, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain.
Pedro
P
Esbrit
Department of Pharmacology and IDM, University of Valencia, Valencia, Spain.|Cooperative Research Thematic Network on Aging and Frailty (RETICEF), ISCIII, Madrid, Spain.
Maria José
MJ
Alcaraz
D000368:Aged; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D010003:Osteoarthritis / Q000378:metabolism* / Q000517:prevention & control; D010006:Osteoblasts / Q000166:cytology; D044162:Parathyroid Hormone-Related Protein / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D015232:Dinoprostone
Inflammation; Osteoarthritis; Osteoblasts; Parathyroid hormone; Senescence; derived peptides; related protein (PTHrP)