Gossypol Promotes Wnt/β-Catenin Signaling through WIF1 in Ovariectomy-Induced Osteoporosis

Abstract

Osteoporosis is one of the most frequent diseases related with age. Previously, we have reported a novel potential drug, gossypol, for the treatment of osteoporosis through its regulation of Wnt/β-catenin signaling. This study aims to identify the detailed mechanism of gossypol in human osteoporosis. Mice injected with gossypol were subjected for RNA-seq analysis and the transcription level of WIF1 was shown to be decreased dramatically in gossypol-treated mice, which was further confirmed by qRT-PCR and western blot analysis. Luciferase reporter assay showed gossypol inhibited the activity of WIF1 and the methylation of WIF1 was significantly upregulated, evidenced by ChIP assay. Cell viability assays demonstrated that gossypol promoted cell proliferation while cotreatment with WIF1 expressing plasmid reversed the effect in a dose- and time-dependent manner. Similarly, cell apoptotic assays and TUNEL assays showed gossypol suppressed cell apoptosis, which was revised by WIF1 overexpression. The mouse model suggested gossypol injection ameliorated osteoporosis, while coinjection of AAV5-WIF1 eliminated the protection effects of gossypol, as evidenced by H&E staining, serum osteocalcin level, serum OPG level, serum RANKL level, bone density, ultimate strength, and postyield displacement. This study is a supplement to the former publication, which reinforced the protection effect of gossypol in human osteoporosis.

Identification of key genes and biological pathways in chronic obstructive pulmonary disease using bioinformatics and next generation sequencing data analysis

“…Signaling pathways include immune system [109], signal transduction [110], extracellular matrix organization [111], adaptive immune system [112], neutrophil degranulation [113], innate immune system [114], metabolism [115], diseases of metabolism [116] and Hemostasis [117] were responsible for advancement of COPD. MPO (myeloperoxidase) [190], CTSD (cathepsin D) [1389], KLF10 [1390], FRZB (frizzled related protein) [1391], DUSP1 [1392], IL1B [1393], CCL11 [1394], LMNA (lamin A/C) [1395], WIF1 [1396], IL1RN [1397], IFNG (interferon gamma) [1398], CX3CL1 [1399], BMP2 [1400], CDKN1A [1401], BMP4 [1402], ICAM1 [1403], CD34 [1404], IL33 [1405], FASLG (Fas ligand) [1406], KDM6B [1407], TNF (tumor necrosis factor) [1408], GDF15 [1409], IL2 [1410], INPP4B [1411], FABP4 [1412], CYP2C19 [1413], CXCR4 [1414], DKK2 [1415], PLCB4 [1416], ANXA1 [1417], DUSP6 [1418], CORIN (corin, serine peptidase) [1419], F8 [1420], DDIT4 [1421], IL1R2 [1422], S100A4…”

Therapeutic approach of natural products that treat osteoporosis by targeting epigenetic modulation

“…The Wnt inhibitory factor 1 (WIF1) was also identified as a critical factor for gossypol treatment. One study confirmed that gossypol suppresses WIF1 levels via methylation of the WIF1 promoter ( Liang et al, 2019 ). Collectively, these findings confirm that gossypol is another potential drug for OP therapy.…”

Wnt Pathway Extracellular Components and Their Essential Roles in Bone Homeostasis

“…The most intriguing pathogenic alterations of this gene are related to its methylation pattern. A proposed treatment against osteoporosis, Gossypol, was observed to promote bone proliferation through the methylation and inhibition of the WIF-1 promoter [ 463 ]. On the other hand, WIF-1 methylation has been associated with bone tumors.…”