Attenuation of Post-Traumatic Osteoarthritis After Anterior Cruciate Ligament Injury Via Inhibition of Hedgehog Signaling.
ADAMTS5 Protein
/ metabolism
Animals
Anterior Cruciate Ligament
/ metabolism
Anterior Cruciate Ligament Injuries
/ pathology
Cartilage, Articular
/ pathology
Core Binding Factor Alpha 1 Subunit
/ metabolism
Disease Models, Animal
Gene Expression Regulation
Hedgehog Proteins
/ metabolism
Knee Joint
/ pathology
Male
Mice
Mice, Knockout
Osteoarthritis
/ genetics
Physical Conditioning, Animal
Signal Transduction
Smoothened Receptor
/ genetics
Tibia
/ physiology
Wounds and Injuries
anterior cruciate ligament
hedgehog
mechanical loading
osteophyte
post-traumatic osteoarthritis
Journal
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
ISSN: 1554-527X
Titre abrégé: J Orthop Res
Pays: United States
ID NLM: 8404726
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
27
03
2019
accepted:
04
10
2019
pubmed:
15
10
2019
medline:
1
7
2020
entrez:
15
10
2019
Statut:
ppublish
Résumé
We aimed to investigate whether post-traumatic osteoarthritis (PTOA) progression is appropriately represented by a PTOA mouse model using a unique climbing cage to add mechanical loading after anterior cruciate ligament (ACL) transection and to determine how Hedgehog signaling inhibition prevents PTOA progression by observing time-dependent morphological changes. This controlled laboratory study histologically compared mice with surgically-induced ACL transection (ACLT) and those with voluntary increased activity in a climbing cage from 1 week postoperatively (ACLT + climbing). We generated conditional knockout (cKO) mice with a deleted Smoothened (Smo) gene. Time-dependent histopathological, immunohistochemical, and gene expression analyses were performed. The ACLT + climbing group showed more severe cartilage defects and massive osteophyte formation than the ACLT group. Smo deletion significantly suppressed PTOA progression. The time-dependent assessment revealed cartilaginous processes of equivalent size at the posterior tibial margin in the Smo cKO and control mice at 4 weeks postoperatively. However, at 8 weeks postoperatively, mature ossifying lesions were detected in the controls but not in Smo cKO mice. In the articular cartilage, ADAMTS5 and RUNX2 expression were observed in hypertrophic chondrocytes near the defective cartilage in controls but not in Smo cKO mice. Climbing exercise after ACLT accelerated PTOA progression more severely not only through increasing joint instability induced by ACLT but also through mechanical loading force induced by climbing exercise. Hedgehog signaling inhibition attenuated PTOA progression by suppressing chondrocyte hypertrophy induced by mechanical loads, to which ACL-deficient athletes are usually exposed. Thus, Hedgehog signaling inhibition may be a therapeutic option to prevent arthritic changes in athletes. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:609-619, 2020.
Substances chimiques
Core Binding Factor Alpha 1 Subunit
0
Hedgehog Proteins
0
Runx2 protein, mouse
0
Smo protein, mouse
0
Smoothened Receptor
0
ADAMTS5 Protein
EC 3.4.24.-
Adamts5 protein, mouse
EC 3.4.24.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
609-619Informations de copyright
© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
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