Acute mobilization and migration of bone marrow-derived stem cells following anterior cruciate ligament rupture.

OBJECTIVE: Little is known regarding acute local and systemic processes following anterior cruciate ligament (ACL) rupture. No study has elucidated whether bone marrow-derived mesenchymal stem cells (MSCs) are mobilized into circulation and recruited to the injured joint. METHODS: In Part 1, Lewis rats were randomized to noninvasive ACL rupture (Rupture) or non-injured (Control) (n = 6/group). After 72 h, whole blood MSC concentration was assessed using flow cytometry. Synovial fluid and serum were assayed for stromal cell-derived factor (SDF)-1α and cartilage degeneration biomarkers, respectively. In Part 2, 12 additional rats were randomized and intravenously-injected with fluorescently-labeled allogenic MSCs. Cell tracking was performed using longitudinal, in vivo and ex vivo near-infrared (NIR) imaging and histology. Synovium SDF-1α and interleukin (IL)-17A immunostaining was performed. Serum was assayed for SDF-1α and 29 other cytokines. RESULTS: In Part 1, there was a significant increase in MSC concentration and synovial fluid SDF-1α in Rupture. No differences in cartilage biomarkers were observed. In Part 2, Rupture had significantly higher NIR signal at 24, 48, and 72 h, indicating active recruitment of MSCs to the injured joint. Ex vivo cell tracking demonstrated MSC localization in the synovium and myotendinous junction (MTJ) of the quadriceps. Injured synovia exhibited increased synovitis grade and higher degree of IL-17A and SDF-1α immunostaining. CONCLUSION: ACL rupture induced peripheral blood mobilization of MSCs and migration of intravenously-injected allogenic MSCs to the injured joint, where they localized in the synovium and quadriceps MTJ.

Articular cartilage degeneration following anterior cruciate ligament injury: a comparison of surgical transection and noninvasive rupture as preclinical models of post-traumatic osteoarthritis.

OBJECTIVE: Post-traumatic osteoarthritis (PTOA) is commonly studied using animal models. Surgical ACL transection is an established model, but noninvasive models may mimic human injury more closely. The purpose of this study was to quantify and compare changes in 3D articular cartilage (AC) morphology following noninvasive ACL rupture and surgical ACL transection. METHODS: Thirty-six rats were randomized to uninjured control, noninvasive ACL rupture (Rupture), and surgical ACL transection (Transection), and 4 and 10 week time points (n = 6 per group). Contrast-enhanced micro-computed tomography (CE-µCT) was employed for AC imaging. Femoral and tibial AC were segmented and converted into thickness maps. Compartmental and sub-compartmental AC thickness and surface roughness (Sa) were computed. OARSI histologic scoring was performed. RESULTS: In both injury groups, zones of adjacent thickening and thinning were evident on the medial femoral condyle, along with general thickening and roughening of femoral and tibial AC. The posterior tibia exhibited drastic thickening and surface degeneration, and this was worse in Transection. Both injury groups had increased AC thickness and Sa compared to Control at both time points, and Transection exhibited significantly higher Sa in every tibial compartment compared to Rupture. Histologic score was elevated in both groups, and the medial femur exhibited the most severe histologic degeneration. CONCLUSIONS: This is the first 3D quantification of preclinical AC remodeling after ACL injury. Both injury models induced similar changes in AC morphology, but Transection exhibited higher tibial Sa and a greater degree of posterior tibial degeneration. We conclude that AC degeneration is a time-, compartment-, and injury-dependent cascade.