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.

Human FGF subfamily is a kind of cytokines that play important roles in cell growth, development, metabolism and tissue disease. 8 There are 22 members in the FGF family (FGF-1-23 in human, lacking FGF-15, because FGF-15 is a mouse homologous gene of human FGF-19 9 ), which can be divided into two categories: paracrine and endocrine. According to the similarity and specificity of its protein structure, FGF family is divided into seven subfamilies, namely FGF-1, belong to the endocrine category. [8][9][10][11] Current studies have shown that FGF members, such as FGF-2, FGF-9, FGF-18 and FGF-19, have been closely implicated into the physiology and pathology of cartilage and they can promote the development of cartilage and bone, 1,9,[12][13][14][15][16] but the specific role of FGF-8 subfamily in the growth and development of cartilage and cartilage disease progression remains partially known.
The FGF-8 subfamily consists of three proteins: FGF-8, FGF-17 and FGF-18. 9,12 Among them, FGF-17 plays a vital role in brain development, 17 while FGF-18 and FGF-8 play important roles in chondrogenesis and osteogenesis. 12,18,19 Considering the limited understandings of The FGF-8 protein was originally identified in a mouse model of androgen-dependent breast cancer by Tanaka in 1992, and thus, FGF-8 protein is also recognized as androgen-induced growth factor (AIGF). 20,21 The FGF-8 is involved in the activation of physiological cellular activities such as cell proliferation and differentiation, cell migration and the survival of early embryonic cells in the human body, 22 and this partially determines its role in the morphological development of human embryos, limb maturation, differentiation and evolution of the nervous system, adolescent hormone regulation in postnatal development. 5,23,24 The human FGF-8 protein includes the isoforms FGF-8A, FGF-8B, FGF-8E and FGF-8F, among which FGF-8B is considered to have the strongest ability to recognize and bind FGFR (Figure 1). FGF-8, especially FGF-8B, exerts different biological effects on humans by binding to different FGFR isoforms. 20 FGF-8 family members show a unique binding affinity for FGF receptors and tissue distribution patterns. 12,22,25 In normal physiology, FGFR consists mainly of 4 members, FGFR1, FGFR2, FGFR3 and FGFR4, with corresponding subclasses of FGFR2 and FGFR3. 8,26 FGF-8 mutual recognition and binding to FGFR results in varying degrees of activation of downstream signalling pathways, such as the RAS/MAPK, MEK-ERK, Wntβ-catenin and PLCγ/Ca 2+ pathways, activating downstream factors such as MSX-1, BMP4 and Wntβcatenin to promote corresponding physiological activities such as angiogenesis and hormonal regulation ( Figure 2). 13,20,[27][28][29][30] can promote angiogenesis and there is angiogenesis in joint inflammation such as osteoarthritis, so we speculated that when FGF-8, especially FGF-8B, is overexpressed, it may potentially promote the occurrence and development of joint inflammation. 20,31,32 All current researches indicate that in-depth insights into the molecular mechanism of the FGF-8 signalling pathway are urgently needed to provide a better understanding of FGF-8 in human growth, inflammatory process and even the potential personalized therapy.

| The cartilage tissue
Cartilage tissue is composed of scattered low-density single chondrocytes and abundant cartilage matrix, which contains no blood vessels, lymphoid tissue or nerves. 33,34 Cartilage is a supportive cellular connective tissue with a tough texture. According to the difference in cartilage matrix, cartilage is divided into three types: hyaline, elastic and fibrous. Among them, hyaline cartilage is widely studied because of its ability to secrete extracellular matrix (ECM). 35 Accumulated evidence has shown that FGF signalling pathways play an important role in cartilage production, maturation and development of subchondral bone. 36,37 Among them, fibroblast growth factor 2 and 19 (FGF-2 and FGF-19) have been studied extensively, but FGF-8 interacted with chondrocytes is not completely understood. Therefore, the molecular mechanism of FGF-8 in cartilage tissue has been extensively investigated experimentally in recent years to determine the interaction between FGF-8 and cartilage tissue.

| The importance of FGF-8 in cartilage physiology
The roles of FGF-8 and FGFR in the development of normal cartilage tissue are manifested in the interaction in the dynamic balance of catabolism and anabolism. 5,[37][38][39][40] In different stages of the growth and development of limbs and joints, different types of

| THE REL ATI ON S HIP B E T WEEN FG F-8 AND CHONDRO C Y TE S IN C ARTIL AG E DISE A SE S
Chondrocytes undergo many processes in developing into mature cartilage tissue, such as cell proliferation, cell differentiation, maturation and hypertrophy, and cartilage stromal cell aggregation. 5,66 There is only a single low-density chondrocyte and extracellular matrix in cartilage tissue. Pathological cartilage formation or the progression of chondrocyte diseases may be related to the abnormal state of chondrocytes and chondrocyte matrix. At present, the relationship between FGF-8 and cartilage diseases has been lucubrated, aiming to provide potential guidance for the diagnosis and treatment of cartilage diseases in future.

| Osteoarthritis (OA)
The expression of FGF-8 is low in mature cartilage tissue.

| CON CLUS I ON S AND PER S PEC TIVE S
Cartilage tissue supports normal body movement and bone formation so the development of cartilage tissue is important for human growth and development. And it has been proved that FGF-8 signalling pathway is considered a vital pathway to regulate early physiological activities in the cartilage formation, including but not limited to promoting migration of mesenchymal stem cells, differentiation into chondrocytes and proliferation of chondrocytes. Considering

ACK N OWLED G EM ENTS
We acknowledged funding support by the National Nature Science

CO N FLI C T O F I NTE R E S T
The authors declare that no competing interests exist.

DATA AVA I L A B I L I T Y S TAT E M E N T
Any data involving this study are available from the corresponding author on request.