Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases

Int J Mol Sci. 2020 Feb 17;21(4):1340. doi: 10.3390/ijms21041340.


: 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.

Keywords: achondroplasia; fibrodysplasia ossificans progressive; osteoarthritis; rheumatoid arthritis.

Publication types

  • Review

MeSH terms

  • Achondroplasia / genetics
  • Achondroplasia / metabolism
  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type I / metabolism
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / metabolism
  • Chondrocytes / metabolism
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Humans
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Ossification, Heterotopic / genetics
  • Ossification, Heterotopic / metabolism
  • Osteoarthritis / genetics*
  • Osteoarthritis / metabolism
  • Parathyroid Hormone-Related Protein / genetics
  • Parathyroid Hormone-Related Protein / metabolism
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism
  • SOXC Transcription Factors / genetics*
  • SOXC Transcription Factors / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Wnt Signaling Pathway / genetics*


  • Core Binding Factor Alpha 1 Subunit
  • Cytokines
  • Hedgehog Proteins
  • Interleukin-1
  • MicroRNAs
  • NF-kappa B
  • Parathyroid Hormone-Related Protein
  • RUNX2 protein, human
  • SOX4 protein, human
  • SOXC Transcription Factors
  • Tumor Necrosis Factor-alpha
  • MTOR protein, human
  • FGFR3 protein, human
  • Receptor, Fibroblast Growth Factor, Type 3
  • TOR Serine-Threonine Kinases
  • ACVR1 protein, human
  • Activin Receptors, Type I