Halofuginone Attenuates Osteoarthritis

Osteoarthritis is one of the most frequent chronic diseases. For instance, Osteoarthritis is a major source of pain. The epidemiology of the disorder is complex and multi-factorial. Interestingly, osteoarthritis is a leading cause of disability. The resultant phenotype includes articular cartilage degeneration, subchondral bone sclerosis and oedema, osteochondral angiogenesis, inflammation and osteophyte formation. Additionally, osteoarthritis joints pain and functional impairment. The aetiology of Osteoarthritis is multifactorial and includes intrinsic and extrinsic factors that propagate a multitude of cellular responses.

Keller TL, et al found that the small molecule Halofuginone attenuated osteoarthritis progression. In this study Halofuginone inhibited subchondral bone TGF-β activity and aberrant angiogenesis. As we all know, Halofuginone is an analogue of Febrifugine. Halofuginone is isolated from the plant Dichroa febrifuga in ancient Chinese herbal medicine.

First of all, Halofuginone binds glutamyl-prolyl-tRNA synthetase (EPRS), inhibiting prolyl-tRNA synthetase activity. Halofuginone induces antiangiogenic effects at several essential stages of angiogenesis, largely through inhibition of matrix metalloproteinase-2 (MMP-2). Hopefully, Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone. Halofuginone potently inhibits the differentiation of pro-inflammatory Th17 cells through activation of the nutrient-sensing amino acid response pathway. Halofuginone also inhibits the development of Th17-driven autoimmunity in a mouse model of multiple sclerosis. Secondly, Halofuginone induces a cellular amino acid starvation response. This response represses global protein synthesis and rapidly depleted NRF2. NRF2 is a transcription factor that activates the expression of cytoprotective genes encoding antioxidative, detoxifying and metabolic enzymes as well as transporters. Moreover, Halofuginone has shown therapeutic promise in clinical trials for fibrotic diseases, such as scleroderma. Halofuginone inhibitis phosphorylation of Smad2/3 and TGF-β-mediated collagen type I synthesis.

Consequently, Halofuginone is a potential preventive therapy for osteoarthritis.