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

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.

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

Figure 1

Therapeutic approaches for rheumatoid arthritis. IL-1α and IL-1β, or TNFα stimulate NF-ĸB through IL-1 receptor (IL-1R) or TNF receptor1 (TNFR1), respectively. This action of IL-1α and IL-1β is inhibited by an IL-1 antagonist (IL-1 Ag). IL-6 stimulates the JAK/STAT pathway through a complex of IL-6 receptor (IL-6R) and gp130. Anti-IL-6R antibody (IL-6R Ab) blocks the activity of IL-6. JAK inhibitors (JAK Inh) also block the JAK/STAT pathway.

Figure 2

Potential therapy for fibrodysplasia ossificans progressive (FOP). A gain-of-function mutation of ACVR1 (mutACVR1) induces ENPP2 expression by activating the Smad pathway. Activin A functions as a ligand of the mutant ACRV1. Secreted ENPP2 stimulates mTOR signaling, consequently causing FOP. mTOR signaling suppresses the effect of mutant ACRV1.

Figure 3

Proposed therapy for achondroplasia (ACH) by C-type natriuretic peptide (CNP). A gain-of-function mutation of FGFR3 (mutFGFR3) stimulates STAT1 and MAPK pathways, both of which inhibit chondrocyte proliferation and differentiation, respectively. CNP inhibits progression of ACH in vivo, however, the precise mechanism is unknown.