Abstract
IntroductionThis study was performed to evaluate the attenuation of osteoarthritic (OA) pathogenesis via disruption of the stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) signaling with AMD3100 in a guinea pig OA model.MethodsOA chondrocytes and cartilage explants were incubated with SDF-1, siRNA CXCR4, or anti-CXCR4 antibody before treatment with SDF-1. Matrix metalloproteases (MMPs) mRNA and protein levels were measured with real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The 35 9-month-old male Hartley guinea pigs (0.88 kg ± 0.21 kg) were divided into three groups: AMD-treated group (n = 13); OA group (n = 11); and sham group (n = 11). At 3 months after treatment, knee joints, synovial fluid, and serum were collected for histologic and biochemical analysis. The severity of cartilage damage was assessed by using the modified Mankin score. The levels of SDF-1, glycosaminoglycans (GAGs), MMP-1, MMP-13, and interleukin-1 (IL-1β) were quantified with ELISA.ResultsSDF-1 infiltrated cartilage and decreased proteoglycan staining. Increased glycosaminoglycans and MMP-13 activity were found in the culture media in response to SDF-1 treatment. Disrupting the interaction between SDF-1 and CXCR4 with siRNA CXCR4 or CXCR4 antibody attenuated the effect of SDF-1. Safranin-O staining revealed less cartilage damage in the AMD3100-treated animals with the lowest Mankin score compared with the control animals. The levels of SDF-1, GAG, MMP1, MMP-13, and IL-1β were much lower in the synovial fluid of the AMD3100 group than in that of control group.ConclusionsThe binding of SDF-1 to CXCR4 induces OA cartilage degeneration. The catabolic processes can be disrupted by pharmacologic blockade of SDF-1/CXCR4 signaling. Together, these findings raise the possibility that disruption of the SDF-1/CXCR4 signaling can be used as a therapeutic approach to attenuate cartilage degeneration.
Highlights
This study was performed to evaluate the attenuation of osteoarthritic (OA) pathogenesis via disruption of the stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) signaling with AMD3100 in a guinea pig OA model
The level of GAG was significantly higher in media collected from explants treated with SDF-1 for 4 days, versus explants treated for 2 days, untreated controls or explants pretreated with antiCXCR4 antibody before SDF-1 incubation. (Figure 1D)
matrix metalloprotease (MMP)-13 activity was increased twofold in the medium of cartilage explants treated with SDF-1, but this upregulation was suppressed completely when the SDF-1 pathway was blocked with anti-CXCR-4 antibody (Figure 1E)
Summary
This study was performed to evaluate the attenuation of osteoarthritic (OA) pathogenesis via disruption of the stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) signaling with AMD3100 in a guinea pig OA model. Chondrocytes are the only cells present in cartilage. They are responsible for the maintenance and repair of Chemokines, which have been less studied in the context of osteoarthritis, are a family of small, soluble chemoattractive cytokines that direct movement of nearby responsive cells. Chemokines have been shown to influence cell morphology, proliferation, differentiation, and other activities through the transmembrane G-protein-coupled receptors [6,7]. SDF-1 activates a wide variety of primary cells by binding to the G-protein-coupled receptor, CXCR4 [7]. SDF-1 is synthesized in the synovium, and CXCR4 is expressed by articular chondrocytes [10]
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