Osipov, B. | bioRxiv Science

bioRxiv2024

Concurrent Joint Contact in Anterior Cruciate Ligament Injury induces cartilage micro-injury and subchondral bone sclerosis, resulting in knee osteoarthritis

ObjectiveAnterior Cruciate Ligament (ACL) injury initiates post-traumatic osteoarthritis (PTOA) via two distinct processes: initial direct contact injury of the cartilage surface during ACL injury, and secondary joint instability due to the ACL deficiency. Using the well-established Compression-induced ACL rupture method (ACL-R) and a novel Non-Compression ACL-R model, we aimed to reveal the individual effects of cartilage compression and joint instability on PTOA progression after ACL injury in mice. DesignTwelve-week-old C57BL/6J male were randomly divided to three experimental groups: Compression ACL-R, Non-Compression ACL-R, and Intact. Following ACL injury, we performed joint laxity testing and microscopic analysis of the articular cartilage surface at 0 days, in vivo optical imaging of matrix-metalloproteinase (MMP) activity at 3 and 7 days, and histological and microCT analysis at 0, 7, 14, and 28 days. ResultsThe Compression ACL-R group exhibited a significant increase of cartilage roughness immediately after injury compared with the Non-Compression group. At 7 days, the Compression group exhibited increased MMP-induced fluorescence intensity and MMP-13 positive cell ratio of chondrocytes. Moreover, histological cartilage degeneration was observable in the Compression group at the same time point. Sclerosis of tibial subchondral bone in the Compression group was more significantly developed than in the Non-Compression group at 28 days. ConclusionsBoth Compression and Non-Compression ACL injury initiated PTOA progression due to joint instability. However, joint contact during ACL rupture also caused initial micro-damage on the cartilage surface and initiated early MMP activity, which could accelerate PTOA progression compared to ACL injury without concurrent joint contact.

molecular biology↗

bioRxiv2020

Systemic Bone Loss Following Myocardial Infarction in Mice is Mitigated by Treatment with a β3 Adrenergic Receptor Antagonist

Myocardial infarction (MI) and osteoporotic fracture (Fx) are leading causes of morbidity and mortality worldwide, and there is epidemiological evidence linking their incidence, suggesting possible crosstalk. MI can exacerbate underlying atherosclerosis through sympathetic nervous system activation and {beta}3 adrenoreceptor-mediated release of hematopoietic stem cells (HSCs), leading to monocytosis. We hypothesized that this same pathway may initiate systemic bone loss following MI, since osteoclasts differentiate from monocytes. In this study, MI was performed in 12-week-old male mice (n=24), and mice were randomized to treatment with a {beta}3-adrenergic receptor antagonist (SR 59230A) or no treatment for 10 days post-operatively; additional mice (n=21, treated and untreated) served as un-operated controls. Bone mineral density (BMD), bone mineral content (BMC), and body composition were quantified at baseline and 10 days post-MI using DXA; at 10 days post-MI circulating monocyte and neutrophil levels were quantified, and the L5 vertebral body and femur were analyzed with micro-computed tomography. We found that MI led to increases in circulating monocyte and neutrophil levels, but contrary to our initial hypothesis, {beta}3-antagonist treatment further increased circulating monocytes compared to untreated mice. BMD and BMC of MI mice decreased at the femur and lumbar spine (-6.9% femur BMD, -3.5% lumbar BMD); {beta}3-antagonist treatment diminished this bone loss response (-5.3% femur BMD, -1.2% lumbar BMD). Similarly, trabecular bone volume was decreased in MI mice compared to control mice, and this bone loss was partially attenuated by {beta}3-antagonist treatment. These results suggest that MI leads to bone loss at both the axial and appendicular skeleton, and that the sympathetic nervous system may be a modulator of this response. This study is the first to mechanistically show bone loss following an ischemic injury; these findings suggest that bone loss and increased fracture risk may be important clinical co-morbidities following MI or other ischemic injuries.

physiology↗