Abstract
Osteoarthritis and rheumatoid arthritis are common cartilage and joint diseases that globally affect more than 200 million and 20 million people, respectively. Several transcription factors have been implicated in the onset and progression of osteoarthritis, including Runx2, C/EBPβ, HIF2α, Sox4, and Sox11. Interleukin-1 β (IL-1β) leads to osteoarthritis through NF-ĸB, IκBζ, and the Zn2+-ZIP8-MTF1 axis. IL-1, IL-6, and tumor necrosis factor α (TNFα) play a major pathological role in rheumatoid arthritis through NF-ĸB and JAK/STAT pathways. Indeed, inhibitory reagents for IL-1, IL-6, and TNFα provide clinical benefits for rheumatoid arthritis patients. Several growth factors, such as bone morphogenetic protein (BMP), fibroblast growth factor (FGF), parathyroid hormone-related protein (PTHrP), and Indian hedgehog, play roles in regulating chondrocyte proliferation and differentiation. Disruption and excess of these signaling pathways cause genetic disorders in cartilage and skeletal tissues. Fibrodysplasia ossificans progressive, an autosomal genetic disorder characterized by ectopic ossification, is induced by mutant ACVR1. Mechanistic target of rapamycin kinase (mTOR) inhibitors can prevent ectopic ossification induced by ACVR1 mutations. C-type natriuretic peptide is currently the most promising therapy for achondroplasia and related autosomal genetic diseases that manifest severe dwarfism. In these ways, investigation of cartilage and chondrocyte diseases at molecular and cellular levels has enlightened the development of effective therapies. Thus, identification of signaling pathways and transcription factors implicated in these diseases is important.
Highlights
Cartilage is an important tissue that functions in skeletal development, tissue patterning, locomotive organs, respiration, and organ support [1,2]
These results demonstrate that the linkage between IL-1 and the Zn2+-Zn2+ importer bZIP transcription factor 8 (ZIP8)-metal regulatory transcription factor 1 (MTF1) axis is important in the onset of osteoarthritis
IL-1 treatment has been shown to downregulate WW domain-containing E3 ubiquitin protein ligase 2 (Wwp2) expression in articular chondrocytes [52]. These findings indicate an anti-pathological role of Wwp2 and/or Micro-RNA 140 (miR-140) in osteoarthritis
Summary
Cartilage is an important tissue that functions in skeletal development, tissue patterning, locomotive organs, respiration, and organ support [1,2]. In this review, we introduce and discuss our recent understanding of the role of intracellular signaling pathways and transcription factors involved in cartilage and joint diseases, as well as potential therapies. Expression of Yes-associated protein (YAP), a major mediator of Hippo signaling, was found to be decreased along with the development of osteoarthritis, whereas YAP activation inhibited the degradation of cartilage tissues in an osteoarthritis model [28]. Metal regulatory transcription factor 1 (MTF1) was identified as a transcriptional regulator of ZIP8, and osteoarthritis phenotypes were attenuated by MTF1 deficiency in cartilage [33] Together, these results demonstrate that the linkage between IL-1 and the Zn2+-ZIP8-MTF1 axis is important in the onset of osteoarthritis
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