Biology subjects

Keenan, C.

Publications and source records attributed to Keenan, C..

4 recordsLinked to original sources

bioRxiv2026

Pathological musculoskeletal characterisation of a new model of spontaneous OA in CD1 mice.

Osteoarthritis (OA) is a whole joint disease involving pathological changes in cartilage, synovium, ligaments, menisci and periarticular muscle. This study provides a comprehensive musculoskeletal characterisation of spontaneous OA in male CD1 mice to evaluate their suitability as a model of naturally occurring disease. Knee joints from 3-4 and 6-8 month old mice were analysed histologically, OARSI scoring and immunohistochemistry for markers of chondrogenesis and endochondral ossification. Quadriceps and gastrocnemius muscles were examined for fibre cross sectional area. CD1 mice displayed mild OA at 3-4 months, progressing to moderate to severe disease by 6-8 months. Cartilage loss, synovial hyperplasia and fibrosis increased across compartments. Anterior cruciate and collateral ligaments, and medial meniscus exhibited marked pathological remodelling, including proteoglycan rich rounded cell regions and evidence of endochondral ossification with increased COL2, SOX9, RUNX2 and ASPN expression. Gastrocnemius muscle showed significant atrophy at 6-8 months, correlating with OA severity, whereas quadriceps atrophy was not significant. These findings establish CD1 mice as a robust spontaneous OA model that recapitulates the multi-tissue complexity of human disease. Because CD1 mice are globally available, cost-effective, genetically diverse and frequently, this model offers a practical and translationally relevant platform for investigating whole-joint organ mechanisms of OA progression and for evaluating therapies aimed at modifying disease across the entire joint.

pathology↗

bioRxiv2024

Sex specific knee joint soft tissue mineralization with Fibrillin-1 mutation in male Tight Skin mice.

Articular soft tissue mineralization and ossification are clear pathological signs of osteoarthritis joints. However their molecular and cellular aetiologies remain largely unknown. TGF-{beta} family members are known contributors to both pathological ossification and osteoarthritis development. In this study, we used a Fibrillin-1 mutant mouse, the Tight Skin mouse (TSK), to define the detrimental effects of abnormal Fbn1 in TSK mice and known high TGF-{beta} activity in joint pathology such as articular soft tissue mineralization and ossification. Knee joints of male and Female TSK and Wild-type (WT) littermates were analysed my micro-CT imaging and histology for articular soft tissue pathologies, as well as OA severity. Both aged (10, 26, 35 and 52wks) and following in vivo non-invasive repetitive joint overloading were used. We find that male TSK mice develop spontaneous soft tissue ossification from 26wks of age, followed by increased osteoarthritis at 1 year-old. In addition, knee joint overloading induced ligament and meniscal mineralisation and ossification in both WT and TSK male mice, but were significantly more severe in TSK knees, including ossification of the patella ligament and synovial lining. In contrast, female TSK knees did not develop more severe soft tissue mineralisation compared to littermate WT mice in neither aged nor overloaded knees. We conclude that Fbn1 mutation, and possibly overactive TGF-{beta} activity in TSK mice, induce articular soft tissue ossification and osteoarthritis in a sex-specific manner. Further studies are needed to confirm the specific signalling involved and the relative protection from female mice from such pathologies.

pathology↗

bioRxiv2021

The anterior cruciate ligament in murine post-traumatic osteoarthritis: markers and mechanics

1Osteoarthritis (OA) is a whole joint disease that affects all knee joint tissues. Ligaments, a matrix-rich connective tissue, play an important mechanical function that stabilises the knee joint and yet their role in OA is not well studied. Recent studies have shown that ligament extracellular matrix (ECM) structure is compromised in the early stages of OA, but it remains unclear how this affects ligament function and biomechanics. In this study, the aim was to investigate the structural, cellular and viscoelastic changes in the anterior cruciate ligament (ACL) in a murine non-invasive post-traumatic OA (PTOA) model. Non-invasive mechanical loading of the knee joint of C57BL/6J mice (10-week-old) was used as a PTOA model. Knee joints were analysed for joint space mineralisation and the ACLs were assessed with histology and mechanical testing. PTOA knee joints had a 33-46% increase in joint space mineralisation and PTOA knee joint ACLs exhibited ECM modifications, including collagen birefringence and COL2 and proteoglycan deposition. ECM changes were associated with cells expressing chondrogenic markers (SOX9 and RUNX2) expanding from the tibial enthesis to the ACL midbody. Viscoelastic and mechanical changes in the ACLs from PTOA knee joints included a 20-21% decrease in tangent modulus at 2MPa of stress, and a decrease strain rate sensitivity at higher strain rates and a significant increase in relaxation during stress-relaxation, but no changes to hysteresis and ultimate load to failure. These results demonstrate that ACL pathology and viscoelastic function is compromised in murine PTOA knee joints and provides further evidence of the important role of ligaments in the knee joint organ in health and disease.

pathology↗

bioRxiv2020

Post-traumatic osteoarthritis development is not modified by postnatal chondrocyte deletion of CCN2.

CCN2 is a matricellular protein involved in several critical biological processes. In particular, CCN2 is involved in cartilage development and in osteoarthritis. CCN2 null mice exhibit a range of skeletal dysmorphisms, highlighting its importance in regulating matrix formation during development, however its role in adult cartilage remains unclear. The aim of this study was to determine the role of CCN2 in postnatal chondrocytes in models of post-traumatic osteoarthritis (PTOA). CCN2 deletion was induced in articular chondrocytes of male transgenic mice at 8 weeks of age. PTOA was induced in knees either surgically or non-invasively by repetitive mechanical loading at 10 weeks of age. Knee joints were harvested, scanned with micro-CT, and processed for histology. Sections were stained with toluidine blue and scored using the OARSI grading system. In the non-invasive model cartilage lesions were present in the lateral femur but no significant differences were observed between wildtype (WT) and CCN2 knockout (KO) mice 6 weeks post-loading. In the surgical model, severe cartilage degeneration was observed in the medial compartments but no significant differences were observed between WT and CCN2 KO mice at 2, 4, and 8 weeks post-surgery. We conclude that CCN2 deletion in chondrocytes did not modify the development of PTOA in mice, suggesting that chondrocyte expression of CCN2 in adults is not a critical player in protecting cartilage from the degeneration associated with PTOA. Summary StatementPost-natal deletion of CCN2 in chondrocytes does not affect the development of post-traumatic osteoarthritis in mice.

pathology↗