Ligamentous injury-induced ankle instability causing posttraumatic osteoarthritis in a mouse model

Li, Junkun; Chen, Zhi; Cheng, Yan; Gao, Chao; Li, Jiaxin; Gu, Xia; He, Fan; Luo, Zong‐Ping; Zhang, Hongtao; Yu, Jia

doi:10.1186/s12891-022-05164-5

Cited by 7 publications

(6 citation statements)

References 49 publications

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“…Foot (paw) print area or pressure, as one of important gait parameters involving pain, is significantly reduced in patients (mice) with ACL injury ( 25 , 45 ). The paw overlap distance, defined as the average overlapping distance of ipsilateral paws across successive strides, is significantly increased in animals with knee or ankle surgeries ( 46 ). Similarly, we found that the wound pain and knee stability affected the values of the two gait parameters, so they showed different characteristics at the early and late healing stages.…”

Section: Discussionmentioning

confidence: 99%

Activation of CGRP receptor–mediated signaling promotes tendon-bone healing

Zhao,

Wu,

Zhang

et al. 2024

Sci. Adv.

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Calcitonin gene-related peptide (CGRP), an osteopromotive neurotransmitter with a short half-life, shows increase while calcitonin receptor-like (CALCRL) level is decreased at the early stage in bone fractures. Therefore, the activation of CALCRL-mediated signaling may be more critical to promote the tendon-bone healing. We found CGRP enhanced osteogenic differentiation of BMSCs through PKA/CREB/JUNB pathway, contributing to improved sonic hedgehog (SHH) expression, which was verified at the tendon-bone interface (TBI) in the mice with Calcrl overexpression. The osteoblast-derived SHH and slit guidance ligand 3 were reported to favor nerve regeneration and type H (CD31 hi EMCN hi ) vessel formation, respectively. Encouragingly, the activation or inactivation of CALCRL-mediated signaling significantly increased or decreased intensity of type H vessel and nerve fiber at the TBI, respectively. Simultaneously, improved gait characteristics and biomechanical performance were observed in the Calcrl overexpression group. Together, the gene therapy targeting CGRP receptor may be a therapeutic strategy in sports medicine.

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Section: Discussionmentioning

confidence: 99%

Activation of CGRP receptor–mediated signaling promotes tendon-bone healing

Zhao,

Wu,

Zhang

et al. 2024

Sci. Adv.

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“…Depending on different populations, up to 70% of patients suffering from lateral ankle sprain develop CAI (Fong et al, 2007;Swenson et al, 2009;Hiller et al, 2012). CAI has also been found to have a higher risk of developing posttraumatic osteoarthritis (Gribble et al, 2016;Liu et al, 2021;Li et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Currently, two ankle sprain models have been developed. The first one is a mouse model by surgically transecting the CFL and ATFL (Kim et al, 2008;Kim et al, 2011;Hubbard-Turner et al, 2013;Wikstrom et al, 2015;Liu et al, 2021;Li et al, 2022). The second one is a rat model induced by manually overextending the ankle repeatedly in the plantarflexion and inversion directions (Koo et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

A new mouse model of ankle instability induced by multiple mechanical sprains with controlled inversion angle and speed

Ching

Chiu

Liao

et al. 2022

Front. Bioeng. Biotechnol.

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Ankle sprain occurs by a sudden and extreme inversion and plantarflexion at the ankle joint to cause ligamentous injuries. A portion of ankle sprain patients experience recurrent ankle sprains and develop chronic ankle instability (CAI). The present CAI animal models are single events with severe ligamentous injury using surgical transection of ligaments or manually overextending the ankle.Purpose: To simulate the mechanical and recurrent sprain injuries in CAI patients, we established a new ankle instability model with multiple ankle injuries using a self-designed machine to sprain the ankle with a controlled inversion angle and speed.Methods: Male C57BL/6J mice were used and respectively subjected to a sham operation, calcaneofibular ligament (CFL) transection, and mechanical ankle sprains. Three mechanical sprains were performed on the 13th and 185th day after the initial mechanical ankle sprain.Results: The first mechanical sprain and CFL transection induced ankle injury as indicated by an average of a 62% decrease in ankle pressure pain threshold and a 114% increase in the ankle thickness compared with the contralateral untreated ankle. The second and third mechanical sprains induced recurrent ankle injuries. The foot slips during beam tests were increased after mechanical ankle sprains but not after CFL transection, indicating the induction of motor balance deficits. Multiple mechanical ankle sprains induced significant gait changes in longer duration of stance (an average of 194% increase), swing (134%), and step cycle (147%) compared with CFL transection or sham operation, and slower walking speed (78% reduction) and shorter step distance (91%) after the third sprain.Conclusion: These results elucidate that multiple mechanical sprains, which induce recurrent ankle injuries, balance deficits, and gait changes, are a good model for investigating the mechanisms of CAI induced by recurrent sprain injuries.

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“…Therefore, mouse models have been widely used to study various joint diseases. Inspired by mouse models with ankle instability and ankle–subtalar joint complex instability, as well as our team's existing techniques and previous research experience [ 16 , 17 ]. We believed that this problem of establishing a mouse model of PTOA caused by subtalar joint instability may be investigated via a similar approach.…”

Section: Introductionmentioning

confidence: 99%

Mouse model of subtalar post-traumatic osteoarthritis caused by subtalar joint instability

et al. 2022

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Background Common ankle sprains are often accompanied by injury to the subtalar joint, which eventually leads to subtalar joint instability. Because the clinical manifestations for subtalar joint instability are similar to ankle joint injuries, these are often overlooked. This study aimed to establish an animal model of subtalar joint instability to study post-traumatic osteoarthritis of the subtalar joint caused by long-term subtalar joint instability and to provide a reference for future clinical research on chronic subtalar joint instability. Methods In all, 24 C57BL/6 male mice were randomly divided into three groups: Sham, cervical ligament (CL) transection and CL + calcaneofibular ligament (CFL) transection groups. One week after surgical operation, all mice were trained to run in the mouse rotation fatigue machine every day. During this period, a balance beam test was used to evaluate the motor level and coordination ability of the mice before the operation and three days, one week, four weeks, eight weeks, and twelve weeks after operation. Further, post-traumatic osteoarthritis of the subtalar joint was quantified via micro-CT and histological staining. Results The mice in the partial ligament transection group took significantly longer than those in the Sham group to pass through the balance beam and showed an increased number of hindfoot slips. Micro-CT analysis showed that the subtalar bone volume fraction in the CL + CFL transection group and CL transection group was 5.8% and 2.8% higher than that in the Sham group, respectively. Histological staining showed obvious signs of post-traumatic osteoarthritis (PTOA) in the subtalar joint of the ligament transection group. Conclusions The transection of CL and CL + CFL can cause instability of the subtalar joint in mice, resulting in a decrease in motor coordination, and long-term instability of the subtalar joint in mice can cause PTOA of the subtalar joint, which is manifested as destruction and loss of articular cartilage.

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Ligamentous injury-induced ankle instability causing posttraumatic osteoarthritis in a mouse model

Cited by 7 publications

References 49 publications

Activation of CGRP receptor–mediated signaling promotes tendon-bone healing

Activation of CGRP receptor–mediated signaling promotes tendon-bone healing

A new mouse model of ankle instability induced by multiple mechanical sprains with controlled inversion angle and speed

Mouse model of subtalar post-traumatic osteoarthritis caused by subtalar joint instability

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