Markers of Pain in 3 Different Murine Models of Posttraumatic Osteoarthritis: A Comparison Using Gait Analysis, Imaging, Histology, and Gene Expression.

BACKGROUND: Animal models play an important role in studying posttraumatic osteoarthritis (PTOA) disease progression. Different models exist, such as destabilization of the medial meniscus (DMM), anterior cruciate ligament (ACL) surgical transection (ACLs), and noninvasive ACL rupture. PURPOSE: To study the effects of PTOA on nociception in 3 different murine models and to relate these findings to macroscopic and microscopic changes in joint tissues. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 42 male C57BL/6 mice, 12 weeks old, were randomly assigned to 4 groups: intact control (n = 10), DMM (n = 10), ACLs (n = 11), and closed ACL rupture (ACLc; n = 11) groups. Gait analysis was performed on 5 mice from the DMM group and 6 mice from ACLs and ACLc groups at 0, 1, 2, 4, 8, and 12 weeks after injury. At the 12-week time point, all mice underwent radiographs and then either micro-computed tomography imaging followed by histology and immunohistochemistry or gene expression analysis of the dorsal root ganglion and tibialis anterior muscle. RESULTS: The peripheral and central pain markers were expressed at significantly higher levels in the synovium of both ACL injury groups when compared with the DMM group. Muscle atrophy genes were significantly upregulated in the ACL injury groups. Pain-related gait behavior started at 4 weeks for the ACL rupture groups and at 12 weeks for the DMM group. High-resolution radiographic imaging and histology demonstrated divergent changes in bone microstructure between the ACLs and DMM groups, suggesting different mechanical loading environments in these models. CONCLUSION: The principal finding of this study is the presence of markers of nociception at both the gene and the protein levels, with earlier expression in the ACL injury groups when compared with the DMM group. The second finding of this study is that the noninvasive ACL rupture model demonstrated changes comparable with those of the commonly used surgical ACL transection model, supporting use of this clinically realistic model in future studies of PTOA. CLINICAL RELEVANCE: Quantitative clinical outcomes (imaging, pain scale, gait changes) related to osteoarthritis severity in an animal study, allowing for better understanding of clinical outcomes of osteoarthritis progression after ACL injuries in humans.

Achilles Tendons Display Region-Specific Transcriptomic Signatures Associated With Distinct Mechanical Properties.

BACKGROUND: Previous studies have examined the transcriptomes and mechanical properties of whole tendons in different regions of the body. However, less is known about these characteristics within a single tendon. PURPOSE: To develop a regional transcriptomic atlas and evaluate the region-specific mechanical properties of Achilles tendons. STUDY DESIGN: Descriptive laboratory study. METHODS: Achilles tendons from 2-month-old male Sprague Dawley rats were used. Tendons were isolated and divided into proximal, middle, and distal thirds for RNA sequencing (n = 5). For mechanical testing, the Achilles muscle-tendon-calcaneus unit was mounted in a custom-designed materials testing system with the unit clamped over the musculotendinous junction (MTJ) and the calcaneus secured at 90° of dorsiflexion (n = 9). Tendons were stretched to 20 N at a constant speed of 0.0167 mm/s. Cross-sectional area, strain, stress, and Young modulus were determined in each tendon region. RESULTS: An open-access, interactive transcriptional atlas was generated that revealed distinct gene expression signatures in each tendon region. The proximal and distal regions had the largest differences in gene expression, with 2596 genes significantly differentially regulated at least 1.5-fold (q < .01). The proximal tendon displayed increased expression of genes resembling a tendon phenotype and increased expression of nerve cell markers. The distal region displayed increases in genes involved in extracellular matrix synthesis and remodeling, immune cell regulation, and a phenotype similar to cartilage and bone. There was a 3.72-fold increase in Young modulus from the proximal to middle region (P < .01) and an additional 1.34-fold increase from the middle to distal region (P = .027). CONCLUSION: Within a single tendon, there are region-specific transcriptomic signatures and mechanical properties, and there is likely a gradient in the biological and functional phenotype from the proximal origin at the MTJ to the distal insertion at the enthesis. CLINICAL RELEVANCE: These findings improve our understanding of the underlying biological heterogeneity of tendon tissue and will help inform the future targeted use of regenerative medicine and tissue engineering strategies for patients with tendon disorders.

Musculoskeletal Consequences of COVID-19.

Coronavirus disease 2019 (COVID-19) is an emerging pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the majority of patients who become infected with SARS-CoV-2 are asymptomatic or have mild symptoms, some patients develop severe symptoms that can permanently detract from their quality of life. SARS-CoV-2 is closely related to SARS-CoV-1, which causes severe acute respiratory syndrome (SARS). Both viruses infect the respiratory system, and there are direct and indirect effects of this infection on multiple organ systems, including the musculoskeletal system. Epidemiological data from the SARS pandemic of 2002 to 2004 identified myalgias, muscle dysfunction, osteoporosis, and osteonecrosis as common sequelae in patients with moderate and severe forms of this disease. Early studies have indicated that there is also considerable musculoskeletal dysfunction in some patients with COVID-19, although long-term follow-up studies have not yet been conducted. The purpose of this article was to summarize the known musculoskeletal pathologies in patients with SARS or COVID-19 and to combine this with computational modeling and biochemical signaling studies to predict musculoskeletal cellular targets and long-term consequences of the SARS-CoV-2 infection.