动物造模,骨关节炎 Z-bio 2023-04-10 628

　　Osteoarthritis is a total joint disease characterized by degeneration of articular cartilage, abnormal remodeling of subchondral bone, osteophyte formation, and joint inflammation. The prevalence of knee osteoarthritis in people aged 65 and above is as high as 50%, and the prevalence of knee osteoarthritis in people aged 75 and above is over 80%.

　　However, the pathogenesis of OA is complex and unclear, and there is currently no effective intervention medication. Joint replacement therapy is mainly used in the late stage.

　　The changes in subchondral bone are closely related to the progression of OA: in the early stage of OA, subchondral bone appears as bone resorption, while in the late stage, it appears as bone sclerosis. There is a close spatiotemporal correlation between subchondral bone lesions and cartilage degeneration.

　　But its mechanism of action has long troubled the academic community:

　　(1) How does abnormal bone remodeling in subchondral bone lead to total joint degeneration?

　　(2) What is the temporary abnormal activation of subchondral bone osteoclast?

　　(3) What are the key molecules that mediate the dialogue between subchondral bone and cartilage in OA?

　　On April 5, 2023, the team of professors Su Jiacan and Jing Yingying from the Research Institute of translational medicine of Shanghai University/the team of Professor Chen Xiao from the Department of Trauma and Orthopaedics of Changhai Hospital published a research article on Science Advancements, entitled Maintaining the Hypoxia Environment of Subchondral Bone Alleviates Osteoarthritis progress.

　　This study is the first time to realize real-time dynamic measurement of the partial pressure of oxygen in the joints of mice in vivo, which confirms that the osteoclast excessively activated by subchondral bone at the early stage of OA promote the formation of H-type blood vessels and cause changes in the microenvironment of joint oxygen, which is a key link in the development of OA. Maintaining the hypoxic microenvironment of subchondral bone can effectively delay the progress of OA.

　　The lead author of the study is Zhang Hao, postdoctoral fellow, Wang Lipeng, postdoctoral fellow Cui Jin, and Dr. Wang Sicheng of translational medicine research institute of Shanghai University. The corresponding author is Professor Su Jiacan, Professor Jing Yingying of translational medicine research institute of Shanghai University, and Professor Chen Xiao of Shanghai Changhai Hospital.

　　Original link: http://doi.org/10.1126/sciadv.abo7868

　　The research team constructed a traumatic osteoarthritis (PTOA) model induced by anterior cruciate ligament resection (ACLT) and Lcp1 gene knockout mice encoding L-Plastin (LPL) protein.

　　In PTOA mice, after 2 weeks of modeling, Micro CT results showed that bone absorption activity was enhanced, TRAP&LPL immunofluorescence showed that osteoclast reached its peak, and LPL changes were consistent with osteoclast.

　　LPL protein mediates the fusion and differentiation of osteoclast. In Lcp1 knockout mice, TRAP staining results indicate that the formation of subchondral osteoclasts in ACLT mice is reduced, and safranine fixation green staining results indicate that cartilage degeneration is significantly alleviated.

　　The angiographic results indicated that in the Lcp1 knockout mice, the volume of subchondral bone vessels was significantly reduced after ACLT modeling. The 18F-FMISO imaging results indicated that the joint oxygen partial pressure was increased during OA. Lcp1 knockout was conducive to maintaining the joint hypoxia microenvironment.

　　Through single-cell sequencing analysis of knee joint chondrocytes in patients with OA, the research team found a group of hypertrophic chondrocytes closely related to the progression of OA, named OA related hypertrophic chondrocytes (OA-HTC). The OA signaling pathway of this group of cells was significantly upregulated, and the HIF1 signaling pathway was significantly inhibited.

　　Further confirmation in ACLT mice that chondrocyte HIF-1 is involved in the progression of OA α Continuous degradation, while Lcp1 knockout can inhibit HIF-1 α Degradation.

　　By building Hif-1 α Knocking down AAV and staining with safranine solid green suggest that knocking down Hif1a can reverse the protective effect of Lcp1 knockout on articular cartilage.

　　Based on the aforementioned HIF-1 α In the important role of protecting joint cartilage, the team uses HIF-1 α Protein stabilizer DMOG intervened in PTOA mice and found that DMOG can delay cartilage degradation and maintain the expression of type 2 collagen in the cartilage matrix.

　　Based on the above confirmation that inhibiting the LPL expression of osteoclast delays the progress of PTOA, the team used LPL protein targeted inhibitor Oxy A to treat PTOA mice, and the results showed that Oxy A can delay articular cartilage calcification and inhibit cartilage matrix degradation.

　　The research team systematically verified that subchondral bone osteoclast were temporarily active, angiogenesis increased, hypoxia microenvironment destroyed, and HIF-1 in the process of PTOA α The phenomenon of degradation can delay the progression of OA by maintaining a joint hypoxic environment.

　　In the future, the team plans to deeply explore the pathogenesis of OA and is committed to improving and developing treatment strategies for OA, in order to provide more clinical conversion opportunities in the field of bone research and build a bridge from basic research to clinical application.