Targeting CD38 to Suppress Osteoarthritis Development and Associated Pain After Joint Injury in Mice

被引:17
|
作者
Gil Alabarse, Paulo [1 ]
Chen, Liang-Yu [1 ,2 ]
Oliveira, Patricia [1 ,2 ]
Qin, Huaping [2 ]
Liu-Bryan, Ru [1 ,2 ]
机构
[1] VA San Diego Healthcare Syst, San Diego, CA 92161 USA
[2] Univ Calif San Diego, La Jolla, CA 92093 USA
关键词
ACTIVATED PROTEIN-KINASE; KNEE OSTEOARTHRITIS; PROGRESSION; INFLAMMATION; MACROPHAGES; METABOLISM; APIGENIN; SIRT1; AMPK;
D O I
10.1002/art.42351
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective. This study was undertaken to determine the role of CD38, which can function as an enzyme to degrade NAD(+), in osteoarthritis (OA) development.Methods. Human knee cartilage from normal donors and OA donors were examined for CD38 expression. "Gain-of-function, " through overexpression of CD38 via transient transfection, and "loss-of-function, " through pharmacologic inhibition of CD38, approaches were used to assess the effects of CD38 on intracellular NAD(+):NADH ratio and catabolic activity in chondrocytes. We also initiated joint injury-induced OA by surgical destabilization of the medial meniscus (DMM) in CD38 knockout mice and wild-type (WT; C57BL/6) mice and in WT male mice in the presence or absence of apigenin treatment. Cartilage degradation, synovial inflammation, subchondral bone changes, and pain behavior were evaluated after DMM surgery. We also examined expression of CD38 and the neuropeptide calcitonin gene-related peptide (CGRP) in knee sections from these mice.Results. CD38 expression was up-regulated in human knee OA cartilage and in chondrocytes stimulated with the proinflammatory cytokine interleukin-1 beta (IL-1 beta). Overexpression of CD38 in chondrocytes resulted in reduced cellular NAD(+):NADH ratio and augmented catabolic responses to IL-1 beta. These effects were reversed by pharmacologic inhibition of CD38. Cartilage degradation and synovial inflammation, associated with increased CD38 expression in cartilage and synovium, osteophyte formation and subchondral bone sclerosis, and pain-like behavior linked to increased CGRP expression in the synovium were observed in WT mice after joint injury. Such effects were significantly reduced in mice deficient in CD38 through either genetic knockout or pharmacologic inhibition.Conclusion. CD38 deficiency exerts OA disease-modifying effects. Inhibition of CD38 has the potential to be a novel therapeutic approach for OA treatment.
引用
收藏
页码:364 / 374
页数:11
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