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Sotrastaurin, a PKC inhibitor, attenuates RANKL-induced bone resorption and attenuates osteochondral pathologies associated with the development of OA.
- Source :
-
Journal of cellular and molecular medicine [J Cell Mol Med] 2020 Aug; Vol. 24 (15), pp. 8452-8465. Date of Electronic Publication: 2020 Jul 11. - Publication Year :
- 2020
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Abstract
- Osteoarthritis (OA) is a common degenerative disease that affects the musculoskeletal structure of the whole joint, which is characterized by progressive destruction of both articular cartilage and subchondral bone. Treatment of the bone pathologies, particularly osteoclast-mediated subchondral bone loss in the early stages of OA, could prevent subsequent cartilage degeneration and progression of OA. In the present study, the PKC inhibitor, Sotrastaurin, was found to inhibit RANKL-induced osteoclast formation in vitro in a dose- and time-dependent manner. In particular, SO exerted its anti-osteoclastic effect predominantly at the early stages of RANKL stimulation, suggesting inhibitory effects on precursor cell fusion. Using mature osteoclasts cultured on bovine bone discs, we showed that SO also exerts anti-resorptive effects on mature osteoclasts bone resorptive function. Mechanistically, SO attenuates the early activation of the p38, ERK and JNK signalling pathways, leeding to impaired induction of crucial osteoclast transcription factors c-Jun, c-Fos and NFATc1. We also showed that SO treatment significantly inhibited the phosphorylation of PKCĪ“ and MARCKS, an upstream regulator of cathepsin K secretion. Finally, in animal studies, SO significantly alleviates the osteochondral pathologies of subchondral bone destruction as well as articular cartilage degeneration following DMM-induced OA, markedly improving OARSI scores. The reduced subchondral bone loss was associated with marked reductions in TRAP(+) osteoclasts in the subchondral bone tissue. Collectively, our data provide evidence for the protective effects of SO against OA by preventing aberrant subchondral bone and articular cartilage changes. Thus, SO demonstrates potential for further development as an alternative therapeutic option against OA.<br /> (© The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
- Subjects :
- Animals
Bone Resorption metabolism
Bone and Bones metabolism
Cartilage Diseases drug therapy
Cartilage Diseases metabolism
Cartilage, Articular drug effects
Cartilage, Articular metabolism
Cattle
Cell Differentiation drug effects
Female
Male
Mice
Mice, Inbred C57BL
Osteoarthritis metabolism
Osteoclasts metabolism
Signal Transduction drug effects
Bone Resorption drug therapy
Bone and Bones drug effects
Osteoarthritis drug therapy
Osteoclasts drug effects
Protein Kinase C antagonists & inhibitors
Pyrroles pharmacology
Quinazolines pharmacology
RANK Ligand metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1582-4934
- Volume :
- 24
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Journal of cellular and molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 32652826
- Full Text :
- https://doi.org/10.1111/jcmm.15404