Attenuation of osteoarthritis via blockade of the SDF-1/CXCR4 signaling pathway
1 Department of Orthopaedics, The Warren Alpert Medical School of Brown University/Rhode Island Hospital, 1 Hoppin Street, Providence, RI 02903, USA
2 Department of Emergency Medicine, The First Affiliated Hospital of Kunming Medical College, 295 Xichang Road, Kunming, Yunnan, 650032, The People's Republic of China
3 Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, The People's Republic of China
4 Department of Orthopaedics, The First Affiliated Hospital of Kunming Medical College, 295 Xichang Road, Kunming, Yunnan, 650032, The People's Republic of China
5 Ge Zhang's Lab, Institute for Advancing Translational Medicine in Bone & Joint Diseases, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong SAR, The People's Republic of China
6 Teaching Division, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong SAR, The People's Republic of China
7 Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, The People's Republic of China
8 Department of Orthopaedic Surgery, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA
Arthritis Research & Therapy 2012, 14:R177 doi:10.1186/ar3930Published: 31 July 2012
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.
OA 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.
SDF-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.
The 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.