Lory William, Chowdhury Nityananda, Wellslager Bridgette, Pandruvada Subramanya, Huang Yan, Yilmaz Özlem, Yu Hong
Department of Biomedical and Community Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Endocrinology, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Cells. 2024 Nov 28;13(23):1971. doi: 10.3390/cells13231971.
CD38, a nicotinamide adenine dinucleotide (NAD) glycohydrolase, increases during infection or inflammation. Therefore, we aimed to evaluate the effects of a CD38 inhibitor (78c) on NAD levels, IL-1β, IL-6, TNF-α cytokine expressions, and osteoclastogenesis. The results show that treatment with 78c on murine BMMs dose-dependently reduced CD38, reversed the decline of NAD, and inhibited IL-1β, IL-6, and TNF-α pro-inflammatory cytokine levels induced by oral pathogen () or () or by advanced glycation end products (AGEs). Additionally, treatment with 78c dose-dependently suppressed osteoclastogenesis and bone resorption induced by RANKL. Treatment with 78c suppressed CD38, nuclear factor kappa-B (NF-κB), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinases (MAPKs) induced by , , or AGEs, and suppressed podosome components (PI3K, Pyk2, Src, F-actin, integrins, paxillin, and talin) induced by RANKL. These results from our studies support the finding that the inhibition of CD38 by 78c is a promising therapeutic strategy to treat inflammatory bone loss diseases. However, treatment with a CD38 shRNA only significantly reduced IL-1β, IL-6, and TNF-α pro-inflammatory cytokine levels induced by AGEs. Compared with controls, it had limited effects on cytokine levels induced by or . Treatment with the CD38 shRNA enhanced RANKL-induced osteoclastogenesis, suggesting that 78c has some off-target effects.
CD38是一种烟酰胺腺嘌呤二核苷酸（NAD）糖水解酶，在感染或炎症期间会增加。因此，我们旨在评估CD38抑制剂（78c）对NAD水平、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）细胞因子表达以及破骨细胞生成的影响。结果表明，用78c处理小鼠骨髓巨噬细胞（BMMs）可剂量依赖性地降低CD38，逆转NAD的下降，并抑制由口腔病原体（ ）或（ ）或晚期糖基化终产物（AGEs）诱导的IL-1β、IL-6和TNF-α促炎细胞因子水平。此外，用78c处理可剂量依赖性地抑制RANKL诱导的破骨细胞生成和骨吸收。用78c处理可抑制由 、 或AGEs诱导的CD38、核因子κB（NF-κB）、磷酸肌醇3激酶（PI3K）和丝裂原活化蛋白激酶（MAPKs），并抑制由RANKL诱导的足体成分（PI3K、Pyk2、Src、F-肌动蛋白、整合素、桩蛋白和踝蛋白）。我们研究的这些结果支持了以下发现：78c抑制CD38是治疗炎症性骨质流失疾病的一种有前景的治疗策略。然而，用CD38短发夹RNA（shRNA）处理仅显著降低了由AGEs诱导的IL-1β、IL-6和TNF-α促炎细胞因子水平。与对照组相比，它对由 或 诱导的细胞因子水平影响有限。用CD38 shRNA处理增强了RANKL诱导的破骨细胞生成，表明78c有一些脱靶效应。
