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Zoledronic acid generates a spatiotemporal effect to attenuate osteoarthritis by inhibiting potential Wnt5a-associated abnormal subchondral bone resorption

This study aimed to determine the effects of zoledronic acid (ZOL) on OA in rats and explored the molecular mechanism of osteoclast activation in early OA. A knee OA rat model was designed by surgically destabilizing the medial meniscus (DMM). Seventy-two male rats were randomly assigned to Sham+pho...

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Autores principales: Ding, Dong, Wang, Limei, Yan, Jiangbo, Zhou, Yong, Feng, Gangning, Ma, Long, Yang, Yong, Pei, Xiuying, Jin, Qunhua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9333271/
https://www.ncbi.nlm.nih.gov/pubmed/35900969
http://dx.doi.org/10.1371/journal.pone.0271485
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author Ding, Dong
Wang, Limei
Yan, Jiangbo
Zhou, Yong
Feng, Gangning
Ma, Long
Yang, Yong
Pei, Xiuying
Jin, Qunhua
author_facet Ding, Dong
Wang, Limei
Yan, Jiangbo
Zhou, Yong
Feng, Gangning
Ma, Long
Yang, Yong
Pei, Xiuying
Jin, Qunhua
author_sort Ding, Dong
collection PubMed
description This study aimed to determine the effects of zoledronic acid (ZOL) on OA in rats and explored the molecular mechanism of osteoclast activation in early OA. A knee OA rat model was designed by surgically destabilizing the medial meniscus (DMM). Seventy-two male rats were randomly assigned to Sham+phosphate-buffered saline (PBS), DMM+PBS, and DMM+ZOL groups; rats were administered with 100 μg/Kg ZOL or PBS, twice weekly for 4 weeks. After 2, 4, 8, and 12 weeks of OA induction, the thickness of the hyaline and calcified cartilage layers was calculated using hematoxylin and eosin staining, degenerated cartilage stained with Safranin O-fast green staining was evaluated and scored, tartrate-resistant acid phosphatase (TRAP)-stained osteoclasts were counted, changes in subchondral bone using micro-computed tomography were analyzed, and PINP and CTX-I levels were detected using enzyme-linked immunosorbent assay. Using these results, 18 male rats were randomly assigned to three groups. Four weeks after surgery, Wnt5a, RANKL, CXCL12, and NFATc1 protein levels were measured in subchondral bone using western blotting, and mRNA levels of genes related to osteoclastogenesis in subchondral bone were measured using quantitative polymerase chain reaction. Bone marrow-derived macrophages were isolated as osteoclast precursors, and cell differentiation, migration, and adhesion were assessed by TRAP staining and Transwell assays, revealing that DMM induced knee OA in rats. Progressive cartilage loss was observed 12 weeks after OA induction. Subchondral bone remodeling was dominated by bone resorption during early OA (within 4 weeks), whereas bone formation was increased 8 weeks later. ZOL suppressed bone resorption by inhibiting Wnt5a signaling in early OA, improved the imbalance of subchondral bone remodeling, reduced cartilage degeneration, and delayed OA progression. Additionally, ZOL delayed OA progression and reduced cartilage degeneration via a spatiotemporal effect in DMM-induced OA. Osteoclast activity in early OA might be associated with Wnt5a signaling, indicating a possible novel strategy for OA treatment.
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spelling pubmed-93332712022-07-29 Zoledronic acid generates a spatiotemporal effect to attenuate osteoarthritis by inhibiting potential Wnt5a-associated abnormal subchondral bone resorption Ding, Dong Wang, Limei Yan, Jiangbo Zhou, Yong Feng, Gangning Ma, Long Yang, Yong Pei, Xiuying Jin, Qunhua PLoS One Research Article This study aimed to determine the effects of zoledronic acid (ZOL) on OA in rats and explored the molecular mechanism of osteoclast activation in early OA. A knee OA rat model was designed by surgically destabilizing the medial meniscus (DMM). Seventy-two male rats were randomly assigned to Sham+phosphate-buffered saline (PBS), DMM+PBS, and DMM+ZOL groups; rats were administered with 100 μg/Kg ZOL or PBS, twice weekly for 4 weeks. After 2, 4, 8, and 12 weeks of OA induction, the thickness of the hyaline and calcified cartilage layers was calculated using hematoxylin and eosin staining, degenerated cartilage stained with Safranin O-fast green staining was evaluated and scored, tartrate-resistant acid phosphatase (TRAP)-stained osteoclasts were counted, changes in subchondral bone using micro-computed tomography were analyzed, and PINP and CTX-I levels were detected using enzyme-linked immunosorbent assay. Using these results, 18 male rats were randomly assigned to three groups. Four weeks after surgery, Wnt5a, RANKL, CXCL12, and NFATc1 protein levels were measured in subchondral bone using western blotting, and mRNA levels of genes related to osteoclastogenesis in subchondral bone were measured using quantitative polymerase chain reaction. Bone marrow-derived macrophages were isolated as osteoclast precursors, and cell differentiation, migration, and adhesion were assessed by TRAP staining and Transwell assays, revealing that DMM induced knee OA in rats. Progressive cartilage loss was observed 12 weeks after OA induction. Subchondral bone remodeling was dominated by bone resorption during early OA (within 4 weeks), whereas bone formation was increased 8 weeks later. ZOL suppressed bone resorption by inhibiting Wnt5a signaling in early OA, improved the imbalance of subchondral bone remodeling, reduced cartilage degeneration, and delayed OA progression. Additionally, ZOL delayed OA progression and reduced cartilage degeneration via a spatiotemporal effect in DMM-induced OA. Osteoclast activity in early OA might be associated with Wnt5a signaling, indicating a possible novel strategy for OA treatment. Public Library of Science 2022-07-28 /pmc/articles/PMC9333271/ /pubmed/35900969 http://dx.doi.org/10.1371/journal.pone.0271485 Text en © 2022 Ding et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ding, Dong
Wang, Limei
Yan, Jiangbo
Zhou, Yong
Feng, Gangning
Ma, Long
Yang, Yong
Pei, Xiuying
Jin, Qunhua
Zoledronic acid generates a spatiotemporal effect to attenuate osteoarthritis by inhibiting potential Wnt5a-associated abnormal subchondral bone resorption
title Zoledronic acid generates a spatiotemporal effect to attenuate osteoarthritis by inhibiting potential Wnt5a-associated abnormal subchondral bone resorption
title_full Zoledronic acid generates a spatiotemporal effect to attenuate osteoarthritis by inhibiting potential Wnt5a-associated abnormal subchondral bone resorption
title_fullStr Zoledronic acid generates a spatiotemporal effect to attenuate osteoarthritis by inhibiting potential Wnt5a-associated abnormal subchondral bone resorption
title_full_unstemmed Zoledronic acid generates a spatiotemporal effect to attenuate osteoarthritis by inhibiting potential Wnt5a-associated abnormal subchondral bone resorption
title_short Zoledronic acid generates a spatiotemporal effect to attenuate osteoarthritis by inhibiting potential Wnt5a-associated abnormal subchondral bone resorption
title_sort zoledronic acid generates a spatiotemporal effect to attenuate osteoarthritis by inhibiting potential wnt5a-associated abnormal subchondral bone resorption
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9333271/
https://www.ncbi.nlm.nih.gov/pubmed/35900969
http://dx.doi.org/10.1371/journal.pone.0271485
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