Systems analysis of avascular necrosis of femoral head using integrative data analysis and literature mining delineates pathways associated with disease

Abstract

Avascular necrosis of femoral head (AVNFH) is a debilitating disease, which affects the middle aged population. Though the disease is managed using bisphosphonate, it eventually leads to total hip replacement due to collapse of femoral head. Studies regarding the association of single nucleotide polymorphisms with AVNFH, transcriptomics, proteomics, metabolomics, biophysical, ultrastructural and histopathology have been carried out. Functional validation of SNPs was carried out using literature. An integrated systems analysis using the available datasets might help to gain further insights into the disease process. We have carried out an analysis of transcriptomic data from GEO-database, SNPs associated with AVNFH, proteomic and metabolomic data collected from literature. Based on deficiency of vitamins in AVNFH, an enzyme-cofactor network was generated. The datasets are analyzed using ClueGO and the genes are binned into pathways. Metabolomic datasets are analyzed using MetaboAnalyst. Centrality analysis using CytoNCA on the data sets showed cystathionine beta synthase and methylmalonyl-CoA-mutase to be common to 3 out of 4 datasets. Further, the genes common to at least two data sets were analyzed using DisGeNET, which showed their involvement with various diseases, most of which were risk factors associated with AVNFH. Our analysis shows elevated homocysteine, hypoxia, coagulation, Osteoclast differentiation and endochondral ossification as the major pathways associated with disease which correlated with histopathology, IHC, MRI, Micro-Raman spectroscopy etc. The analysis shows AVNFH to be a multi-systemic disease and provides molecular signatures that are characteristic to the disease process.

Adenosine deaminase modulates metabolic remodeling and orchestrates joint destruction in rheumatoid arthritis

“…Alkaline phosphatase (ALP) staining. The multipotent ability of MSCs to differentiate into osteoblasts in an osteogenic medium was assessed by the ALP staining [112][113][114] . After the 70% confluency was reached, cells were exposed to ADA and cultured for 7 days with regular change of media every 48 h. At the end of the 7th day, the spent medium was discarded and the cells washed twice with phosphate buffer saline (PBS).…”

“…Alizarin red S (ARS) staining. ARS staining was done to estimate the mineralization of osteoblasts and to assess the impact of ADA treatment on mineralization 112,114 . After 70% confluency was reached in the osteogenic medium in a 35 mm dish, cells were treated with ADA and then cultured for 21 days with regular change of media every 48 h. The spent medium was aspirated at the end of 21 days without disturbing the monolayer of cells and washed with PBS.…”

Transcriptomic analysis reveals genetic factors regulating early steroid-induced osteonecrosis of the femoral head

“…[ 12 , 13 ] Interestingly, FPR2 antagonist WRW4 or FPR2 deficiency were shown to markedly reverse inhibition of Family with sequence similarity 19 member A5-inducedosteoclastogenesis, indicating that FPR2 plays an important role in regulation of osteoclastogenesis as well as occurrence and development of SONFH disease. [ 9 , 14 ]…”

“…[12,13] Interestingly, FPR2 antagonist WRW4 or FPR2 deficiency were shown to markedly reverse inhibition of Family with sequence similarity 19 member A5-inducedosteoclastogenesis, indicating that FPR2 plays an important role in regulation of osteoclastogenesis as well as occurrence and development of SONFH disease. [9,14] Integrin alpha-X/beta-2, which is encoded by ITGAX, is a receptor that recognizes the G protein-coupled receptor sequence in fibrinogen, thereby mediating cell-cell interactions during inflammatory responses. Functionally, it plays an important role in monocyte adhesion and chemotaxis.…”

Nucleotides modulate synoviocyte proliferation and osteoclast differentiation in macrophages with potential implications for rheumatoid arthritis

“…Further, many metabolic and signaling pathways are found to be deregulated with potential implications for cartilage cell death, synoviocyte proliferation, inflammation, and differentiation of macrophages into osteoclasts (Guo et al 2017;Li et al 2018Li et al , 2020. Analysis of multi-omic data alone or in conjunction with immunohistochemistry or validation by cell culture models has been used to understand diseases such as osteonecrosis, liver diseases, glaucoma, and rheumatoid arthritis (Naik et al 2020;Naik and Sivaramakrishnan 2021;Pulukool et al 2021;Saha et al 2021;Sai Krishna et al 2021).…”