PDGFRB as a potential therapeutic target of ankylosing spondylitis: validation following bioinformatics analysis

Abstract

Ankylosing spondylitis (AS) is a chronic, progressive, and inflammatory disease that mainly affects the central axis joint. Although this disease has already been well documented and studied, its pathogenesis is still not well understood. This study aimed to screen and identify key candidate genes involved in the progression of AS. For this purpose, expression profiles of GSE39340 and GSE41038 were downloaded from the Gene Expression Omnibus and displayed in the form of volcano plots and heatmaps. Differentially expressed genes (DEGs) were identified by the Limma package in R and functional enrichment analyses were performed. Moreover, STRING and Cytoscape were utilized to construct protein-protein interaction (PPI) networks and screen significant modules. Immunohistochemistry (IHC) in tissue chips of AS and normal human synovial tissues was performed to confirm the major proteins associated with its development. Western blotting (WB) and alizarin red staining were applied to validate the expression level of platelet-derived growth factor receptor beta (PDGFRB) and function during osteogenesis differentiation of fibroblasts in AS. A total of 256 DEGs were screened, including 191 up-regulated genes and 65 down-regulated genes. The enriched functions of these identified genes mainly included adherens junction, focal adhesion, and cell-substrate adherens junction. The pathways most highly associated with the progression of AS were TGF-β signaling pathway, the Hippo signaling pathway, and the AGE-RAGE signaling pathway. In addition, IHC showed that mitogen-activated protein kinase 1 (MAPK1), C-X-C motif chemokine receptor 4 (CXCR4), and PDGFRB were highly expressed in AS. PDGFRB was found upregulated during osteogenesis of fibroblasts and stimulates osteogenesis in AS. These findings may improve our understanding of the molecular mechanisms controlling AS. Pharmacological targeting of PDGFRB may initiate a possible suppression of bone formation in AS.

Platelet-Derived Growth Factor B Is a Key Element in the Pathological Bone Formation of Ankylosing Spondylitis

“…Consistent with a previous report, (41) PDGFRB expression was relatively high in AS osteoprogenitors (Fig. 3E), so we compared the ALP activity and type 1/3 collagen responsiveness of AS enthesis cells in response to PDGFA, PDGFAB, or PDGFB.…”

Differentially expressed protein‐coding genes in ankylosing spondylitis: Emerging insights into pathogenesis and therapeutic approaches

“…Moreover, recombinant PDGFB administration enhanced enthesis cells' bone mineralization, which was evident in AS, whereas PDGFRB inhibition effectively inhibited PDGFB's capacity to trigger bone mineralization. A potential suppression of bone growth in AS may commence with pharmacological targeting of PDGFRB 131,132 . It was reported that the Wnt pathway contributes to both homeostasis and bone formation.…”

“…A potential suppression of bone growth in AS may commence with pharmacological targeting of PDGFRB. 131,132 It was reported that the Wnt pathway contributes to both homeostasis and bone formation.…”

Fibroblast Insights into the Pathogenesis of Ankylosing Spondylitis

“…C‑X‑C chemokine receptor type 4 (CXCR4) was upregulated in AS and led to increasing ossification and growth rates of ASFs. 90 , 91 In contrast, inorganic pyrophosphate transport regulator Gene (ANKH) overexpression inhibited viability, mineralization, and ossification in ASFs. 92 Both of the above findings may indicate a new way to study ASFs via Wnt signaling.…”

“… 111 In addition, mitogen-activated protein kinase 1 (MAPK1) was also observed to increase in synovial ASFs. 91 …”