Halofuginone

Abstract: Halofuginone was recently shown to inhibit the differentiation of T helper 17 (TH17) cells, which are associated with autoimmune diseases. The demonstration that halofuginone inhibits prolyl-tRNA synthetase activity explains the observed activation of the amino acid response pathway in TH17 cells and identifies amino acid restriction pathways as potential drug targets in inflammatory disease.

Abstract: Objectives Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models. Methods 3-month-old male C57BL/6J (wild type; WT) mice and Lewis rats were randomised to sham-operated, ACLT-operated, treated with vehicle, or ACLT-operated, treated with halofuginone. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Immunostaining, flow cytometry, RT-PCR and western blot analyses were conducted to detect relative protein and RNA expression. Bone micro CT (μCT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone. Results Halofuginone attenuated articular cartilage degeneration and subchondral bone deterioration, resulting in substantially lower OARSI scores. Specifically, we found that proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated ACLT rodents compared with vehicle-treated ACLT controls. Halofuginone reduced collagen X (Col X), matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5) and increased lubricin, collagen II and aggrecan. In parallel, halofuginone-attenuated uncoupled subchondral bone remodelling as defined by reduced subchondral bone tissue volume, lower trabecular pattern factor (Tb.pf) and increased thickness of subchondral bone plate compared with vehicle-treated ACLT controls. We found that halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone. Conclusions Halofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA.

Abstract: 1. Fibrosis is characterized by extracellular matrix deposition, of which collagen type I is the major constituent. The progressive accumulation of connective tissue resulted in destruction of normal tissue architecture and function. 2. Fibrosis is a common response to various insults or injuries and can be the outcome of any perturbation in the cellular function of any tissue. 3. Halofuginone was found to inhibit collagen α1(I) gene expression and collagen synthesis in a variety of cell cultures including human fibroblasts derived from patients with excessive skin collagen type I synthesis. 4. Halofuginone was found to inhibit collagen α1(I) gene expression and collagen synthesis in animal models characterized by excessive deposition of collagen. In these models, fibrosis was induced in various tissues such as skin, liver, lung, etc. Halofuginone was injected intraperitoneally, added to the foodstuff or applied locally. 5. Halofuginone decreased skin collagen in a chronic graft-versus-host disease patient. 6. The ability of extremely low concentrations of halofuginone to inhibit collagen α1(I) synthesis specifically and transiently at the transcriptional level suggests that this material fulfills the criteria for a successful and effective anti-fibrotic therapy.