The role of fibroblast growth factor 8 in cartilage development and disease

Abstract

Fibroblast growth factor 8 (FGF-8), also known as androgen-induced growth factor (AIGF), is presumed to be a potent mitogenic cytokine that plays important roles in early embryonic development, brain formation and limb development. In the bone environment, FGF-8 produced or received by chondrocyte precursor cells binds to fibroblast growth factor receptor (FGFR), causing different levels of activation of downstream signalling pathways, such as phospholipase C gamma (PLCγ)/Ca²⁺ , RAS/mitogen-activated protein kinase-extracellular regulated protein kinases (RAS/MAPK-MEK-ERK), and Wnt-β-catenin-Axin2 signalling, and ultimately controlling chondrocyte proliferation, differentiation, cell survival and migration. However, the molecular mechanism of FGF-8 in normal or pathological cartilage remains unclear, and thus, FGF-8 represents a novel exploratory target for studies of chondrocyte development and cartilage disease progression. In this review, studies assessing the relationship between FGF-8 and chondrocytes that have been published in the past 5 years are systematically summarized to determine the probable mechanism and physiological effect of FGF-8 on chondrocytes. Based on the existing research results, a therapeutic regimen targeting FGF-8 is proposed to explore the possibility of treating chondrocyte-related diseases.

Keywords: FGF-8; cartilage; chondrocyte; osteoarthritis; skeletal system.

FIGURE 1

Structure of FGF‐8. (A) The FGF‐8 gene is a six‐part segment on chromosome 10, of which 1A, 1B, 1D and 3 are composed of two smaller segments. (B) FGF‐8a, FGF‐8b, FGF‐8e and FGF‐8f in humans are all encoded by FGF gene fragments 1B, 2 and 3, and the difference is in the composition of the 1C and 1D segments

FIGURE 2

FGF‐8‐related signalling pathway. (A) The binding of FGF‐8 molecules to FGFR activates a series of signalling pathways, such as PI3K/AKT, PLCγ/Ca²⁺, RAS/MAPK, MEK‐ERK and Wnt‐β‐catenin‐Axin2. (B) The MAPK‐ERK‐MEK pathway and Wnt signalling pathway induced by FGF‐8 signalling exert both promoting and inhibitory effects and jointly coordinate angiogenesis, tissue development and hormone regulation in the body. (C) The Wnt signalling pathway and JNK signalling pathway also interact through the activation of FGF‐8 signalling pathway

FIGURE 3

Role of FGF‐8 in normal cartilage. (A) In the initial stage of chondrogenesis, mesenchymal cells from the neural crest migrate towards the articular site through the actions of FGF‐8, SHH and FGFR1, and differentiate into chondrogenic precursors. Chondrocytes then undergo early cell proliferation through mechanisms mediated by FGF‐8, FGFR3 and FGFR1. (B) Four layers of chondrocytes have been identified, among which FGFR1 is mainly expressed in mature chondrocytes and hypertrophic chondrocytes, while FGFR3 is expressed at higher levels in surface chondrocytes with more active proliferation. (C) In the process of cartilage development, FGFR3 both promotes and inhibits cartilage formation. In the early stage of chondrogenesis, the interaction of FGFR3 and FGF‐8 induces the expression of SOX9, COL2A1 and other chondrocyte markers and promotes the proliferation and differentiation of chondrocytes and the construction of extracellular matrix. FGF‐8 and FGFR3 induce the expression of osteoblastic markers such as Runx2 and Twist2, degrade aggrecan, and inhibit the synthesis of extracellular matrix by chondrocytes. Moreover, FGF‐8 and FGFR3 promote the apoptosis of chondrocytes by activating caspase3/9. These processes result in a dynamic balance of cartilage production and degradation in normal mature articular cartilage

FIGURE 4

Role of FGF‐8 in osteoarthritis cartilage. (A) SDC4, which encodes Syndecan‐4, is overexpressed in cartilage from subjects with osteoarthritis, leading to the overexpression of its downstream putative factor MMP‐3. MMP‐3 degrades type II collagen and aggrecan in articular cartilage, leading to progressive cartilage damage. Meanwhile, tissue inhibitor of metalloproteinases 3 (TIMP‐3) and TIMP‐1, which limit MMP‐3, is downregulated, leading to chondrocyte damage. (B) Other factors, such as chondrocyte ageing, oxidative stress or inflammation, also inhibit the synthesis of glucosaminoglycans and type II collagen fibres and upregulate the expression of type I collagen, matrix metalloproteinase‐3 and proinflammatory cytokines through the activation of mitogen‐activated protein kinase (MAPK) and MAPK/ERK signalling pathways. (C) In the osteoarthritis model, the degradation of chondrocyte extracellular matrix and the release of the degraded matrix into synovial tissue, as well as the formation of inflammatory blood vessels, are the main causes of disease progression