BMP7 ameliorates intervertebral disc degeneration in type 1 diabetic rats by inhibiting pyroptosis of nucleus pulposus cells and NLRP3 inflammasome activity

Abstract

Background Accumulating evidence indicates that intervertebral disc degeneration (IDD) is associated with diabetes mellitus (DM), while the underlying mechanisms still remain elusive. Herein, the current study sought to explore the potential molecular mechanism of IDD in diabetic rats based on transcriptome sequencing data. Methods Streptozotocin (STZ)-induced diabetes mellitus type 1 (T1DM) rats were used to obtain the nucleus pulposus tissues for transcriptome sequencing. Next, differentially expressed genes (DEGs) in transcriptome sequencing data and GSE34000 microarray dataset were obtained and intersected to acquire the candidate genes. Moreover, GO and KEGG enrichment analyses were performed to analyze the cellular functions and molecular signaling pathways primarily regulated by candidate DEGs. Results A total of 35 key genes involved in IDD of T1DM rats were mainly enriched in the extracellular matrix (ECM) and cytokine adhesion binding-related pathways. NLRP3 inflammasome activation promoted the pyroptosis of nucleus pulposus cells (NPCs). Besides, BMP7 could affect the IDD of T1DM rats by regulating the inflammatory responses. Additionally, NPCs were isolated from STZ-induced T1DM rats to illustrate the effects of BMP7 on IDD of T1DM rats using the ectopic expression method. Both in vitro and in vivo experiments validated that BMP7 alleviated IDD of T1DM rats by inhibiting NLRP3 inflammasome activation and pyroptosis of NPCs. Conclusion Collectively, our findings provided novel mechanistic insights for understanding of the role of BMP7 in IDD of T1DM, and further highlighted BMP7 as a potential therapeutic target for preventing IDD in T1DM.

From hyperglycemia to intervertebral disc damage: exploring diabetic-induced disc degeneration

“…The results showed that BMP7 could be used as a core gene, and NLRP3 inflammasome and pyroptosis related markers were significantly increased in NP cells. Further experimental detection showed that BMP7 inhibits the activation of NLRP3 inflammasome and cell pyroptosis processes, thereby slowing down the IDD of T1D rats ( 55 ). In addition, in T1D mice, higher levels of ADAMTS were shown in the intervertebral disc matrix, which mediated glycan fragmentation and IVD apoptosis ( 56 ).…”

Development and Degeneration of the Intervertebral Disc—Insights from Across Species

“…Diabetes mellitus has been implicated as an indicator/contributor to IVDD. To understand diabetes mellitus type 1 (T1DM) induced IVDD, Yu et al confirmed IVDD in streptozotocin (STZ)-induced T1DM rats and performed NP transcriptome analysis in conjunction with microarray screening to identify genes relevant to IVDD in the T1DM rats [ 123 ]. This resulted in 35 potential genes of interest which were enriched in ECM, cytokine adhesion binding, and displayed prominent molecular function in apoptosis regulation and morphogenesis [ 123 ].…”

“…To understand diabetes mellitus type 1 (T1DM) induced IVDD, Yu et al confirmed IVDD in streptozotocin (STZ)-induced T1DM rats and performed NP transcriptome analysis in conjunction with microarray screening to identify genes relevant to IVDD in the T1DM rats [ 123 ]. This resulted in 35 potential genes of interest which were enriched in ECM, cytokine adhesion binding, and displayed prominent molecular function in apoptosis regulation and morphogenesis [ 123 ]. Interaction analysis of the 35 top differentially expressed genes (DEG) revealed Bmp7 , Ripk4 , Wnt4 , Timp1 , Col11a1 , Acp5 , V dr , Col8a1 , Aldh1a1 , and Thbs4 as the ten core genes in IVDD in STZ induced T1DM rats in descending enrichment [ 123 ].…”

“…This resulted in 35 potential genes of interest which were enriched in ECM, cytokine adhesion binding, and displayed prominent molecular function in apoptosis regulation and morphogenesis [ 123 ]. Interaction analysis of the 35 top differentially expressed genes (DEG) revealed Bmp7 , Ripk4 , Wnt4 , Timp1 , Col11a1 , Acp5 , V dr , Col8a1 , Aldh1a1 , and Thbs4 as the ten core genes in IVDD in STZ induced T1DM rats in descending enrichment [ 123 ]. Further ELISA results found pyroptosis-related proteins NLRP3, IL18, IL1β, and gasdermin-D had significantly higher expression in T1DM rats compared to controls suggesting the potential involvement of NP pyroptosis in IVDD in T1DM rats [ 123 ].…”

Sterile inflammation and the NLRP3 inflammasome in cardiometabolic disease

“… [ 49 ] HFD-fed, Fat-1 transgenic mice NLRP3 Increased HFD-induced expression of NLRP3, production of IL-1β and IL-18, and increased activity of caspase-1 in adipose tissue [ 50 ] HFD-fed, or STZ-induced diabetic Sprague–Dawley rats NLRP3 Increased expression of NLRP3 inflammasome components (NLRP3, ASC, caspase-1, IL-1β), NF-kB, and Nrf2 in liver [ 51 ] T1D Blood mononuclear cells (PBMCs) from T1DM patients NLRP1, NLRP3 Lower NLRP1, NLRP3, caspase-1 and IL-1β expressions. [ 52 ] STZ-induced T1DM rat NLRP3 Increased NLRP3, IL-18, IL1β and GSDM-D protein levels in nucleus pulposus tissues [ 53 ] NAFLD Liver and primary hepatocyte from HFD-fed mice NLRP3 Increased expressions of NLRP3, ASC, caspase-1, and increased caspase-1 activity and IL-1β level [ 54 ] Visceral adipose tissue from NAFLD/NASH patients NLRP4, NLRP6 Downregulated NLRP4, IL-1β, and upregulated NLRP6 expression in visceral adipose tissue, and increased circulating IL-18 levels in patients with pericellular fibrosis. [ 55 ] Liver samples from NAFLD patients, and ob/ob or Nlrp2 −/− mice NLRP2 Decreased mRNA and protein expression of Nlrp2 in NAFLD patient, and Nlrp2 −/− enhanced HFD-induced metabolic syndrome and insulin resistance.…”