Inhibition of SDF-1α/CXCR4 Signalling in Subchondral Bone Attenuates Post-Traumatic Osteoarthritis.

Xuejun Zhang,Qing Yang,Fei Xu,Fengjing Guo,Liang Qin,Yonghui Dong,Peng Cheng,Hui Liu,Anmin Chen,Hui Huang

doi:10.3390/ijms17060943

Abstract

Previous studies showed that SDF-1α is a catabolic factor that can infiltrate cartilage, decrease proteoglycan content, and increase MMP-13 activity. Inhibiting the SDF-1α/CXCR4 signalling pathway can attenuate the pathogenesis of osteoarthritis (OA). Recent studies have also shown that SDF-1α enhances chondrocyte proliferation and maturation. These results appear to be contradictory. In the current study, we used a destabilisation OA animal model to investigate the effects of SDF-1α/CXCR4 signalling in the tibial subchondral bone and the OA pathological process. Post-traumatic osteoarthritis (PTOA) mice models were prepared by transecting the anterior cruciate ligament (ACLT), or a sham surgery was performed, in a total of 30 mice. Mice were treated with phosphate buffer saline (PBS) or AMD3100 (an inhibitor of CXCR4) and sacrificed at 30 days post ACLT or sham surgery. Tibial subchondral bone status was quantified by micro-computed tomography (μCT). Knee-joint histology was analysed to examine the articular cartilage and joint degeneration. The levels of SDF-1α and collagen type I c-telopeptidefragments (CTX-I) were quantified by ELISA. Bone marrow mononuclear cells (BMMCs) were used to clarify the effects of SDF-1α on osteoclast formation and activity in vivo. μCT analysis revealed significant loss of trabecular bone from tibial subchondral bone post-ACLT, which was effectively prevented by AMD3100. AMD3100 could partially prevent bone loss and articular cartilage degeneration. Serum biomarkers revealed an increase in SDF-1α and bone resorption, which were also reduced by AMD3100. SDF-1α can promote osteoclast formation and the expression oftartrate resistant acid phosphatase (TRAP), cathepsin K (CK), and matrix metalloproteinase (MMP)-9 in osteoclasts by activating the MAPK pathway, including ERK and p38, but not JNK. In conclusion, inhibition of SDF-1α/CXCR4signalling was able to prevent trabecular bone loss and attenuated cartilage degeneration in PTOA mice.

Highlights

Osteoarthritis (OA) is the most common joint disease, afflicting mainly the hips and knees, characterised by joint pain and loss of function
We examined the tibial subchondral bone changes in the anterior cruciate ligament (ACLT) OA animals
The total subchondral bone tissue volume (TV) increased by more than 13.6% in ACLT mice compared with the sham-operated controls

Summary

Introduction

Osteoarthritis (OA) is the most common joint disease, afflicting mainly the hips and knees, characterised by joint pain and loss of function. Increasing evidence suggests that OA is a disease of the whole joint [1,2]; the cartilage, synovium, and ligaments, and the bone and bone marrow, especially in PTOA, which represents ~12% of symptomatic OA cases. In PTOA patients, articular chondrocytes and subchondral bone cells perceive acute stress, whereas subchondral bone changes can usually be observed before articular cartilage degeneration [2,3,4,5]. Increasing evidence suggests that subchondral bone turnover and its interactions with the articular cartilage are more important than previously thought. The relationship between high subchondral bone turnover and articular cartilage degeneration may provide a new opportunity to slow down or prevent PTOA progression [2,6,7,8,9]

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Results

Conclusion