Attenuation of cartilage pathogenesis in post-traumatic osteoarthritis (PTOA) in mice by blocking the stromal derived factor 1 receptor (CXCR4) with the specific inhibitor, AMD3100

Abstract

Objective SDF-1 was found to infiltrate cartilage, decrease proteoglycan content, and increase MMP-13 activity after joint trauma. In this study, we tested the hypothesis that interference of the SDF-1/CXCR4 signaling pathway via AMD3100 can attenuate pathogenesis in a mouse model of PTOA. We also tested the predictive and confirmatory power of fluorescence molecular tomography (FMT). Methods AMD3100 was continuously delivered via mini-osmotic pumps. The extent of cartilage damage after AMD3100 or PBS treatment was assessed by histological analysis two months after PTOA was induced by surgical destabilization of the medial meniscus (DMM). Biochemical markers of OA were assessed via immunohistochemistry and in vivo fluorescence molecular tomography (FMT). Regression analysis was used to validate the predictive power of FMT measurements. Results Safranin-O staining revealed significant OA damage in the DMM/PBS mice, while the DMM/AMD3100 treated mice showed a significantly reduced response with minimal pathology. Immunohistochemistry showed that AMD3100 treatment markedly reduced typical OA marker expression in chondrocytes. FMT measurements showed decreased cathepsins and MMP activity in knee joints after treatment. Conclusion The results demonstrate that AMD3100 treatment attenuates PTOA. AMD3100 presents a viable and expedient option for OA therapy given the drug's FDA approval and well-known safety profile.

CXCL12/CXCR4 Axis Regulates Aggrecanase Activation and Cartilage Degradation in a Post-Traumatic Osteoarthritis Rat Model

“…In a murine model of OA, less severe damage was observed in the DMM/AMD3100-treated group than in DMM/PBS-treated controls, indicating that AMD3100 effectively prevented PTOA-associated articular cartilage damage (Figure 2a). These results are consistent with earlier studies that showed that increased CXCL12/CXCR4 expression leads to reduced MMP expression and reduced matrix degradation [12,27], while inhibiting cartilage pathogenesis attenuated by the CXCL12/CXCR4 axis, increasing the overall severity of OA [18,28]. This is the first study that has focused on the role of the CXCL12/CXCR4 pathway on aggrecanase-mediated cartilage loss.…”

“…Although the mechanism of release remains poorly understood, overproduction of CXCL12 has been associated with a range of inflammatory cytokines, including IL-1β, IL-17, HIF-1α, and TNF-α [13,14,15]. The CXCL12/CXCR4 axis plays a pivotal role in the injury and repair of cartilage by acting as a chemoattractant of cells involved in inflammation and stem cell migration [5,16,17,18,19,20,21]. …”

Novel Insights into Osteoarthritis Joint Pathology from Studies in Mice

“…Interestingly, although some chemokines such as CCR5 and CXCR4 drive cartilage destruction in DMM-induced OA [47,48], not all chemokine signaling is bad for cartilage. A recent study by Sherwood et al investigated the role of CXCR2 in cartilage health and disease.…”

A novel therapeutic strategy for cartilage diseases based on lipid nanoparticle-RNAi delivery system

“…Then, 8-week-old C57BL6 male mice (n=5) were injected with 20 μL LNP-beacon (2.5 μM) in the right knee joint and 20 μL free beacon (2.5 μM) in the left knee joint. Then, mice were monitored for 72 hours post-intra-articular injection by fluorescence molecular tomography (FMT), a noninvasive and quantitative fluorescence-based technology with high molecular specificity and sensitivity for 3D tissue imaging of live animals, 9,27,28 at a wavelength of 680 nm to confirm the LNPs' transfection reliability. The knee cartilage was harvested 72 hours after injection to confirm the presence of beacon in the cartilage cells by confocal microscopy.…”