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Table of Contents
Year : 2019  |  Volume : 62  |  Issue : 1  |  Page : 2-10

Fibroblast growth factors: Potential novel targets for regenerative therapy of osteoarthritis

1 Department and Graduate Institute of Aquaculture, National Kaohsiung University of Science and Technology, Kaohsiung, Taiwan
2 Graduate Institute of Biomedical Sciences, College of Medicine; Center for Molecular Medicine; Cancer Biology and Drug Discovery Ph.D. Program, China Medical University, Taichung, Taiwan
3 Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
4 Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Date of Submission03-Dec-2018
Date of Decision29-Jan-2019
Date of Acceptance07-Feb-2019
Date of Web Publication22-Feb-2019

Correspondence Address:
Prof. Shaw-Jenq Tsai
Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 70101
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CJP.CJP_11_19

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Osteoarthritis (OA) is a degenerative joint disorder and is the leading cause of disability of people, which negatively impact people's physical and mental health. Although OA causes great socioeconomic burden and individual suffering, no effective treatment options are provided so far. This is partially resulted from poor regenerative activity of articular cartilage and our incomplete understanding of the underlying mechanism of OA. Traditional drug therapies such as acetaminophen and opioids are effective in relieving pain but do not reverse cartilage damage and are often associated with adverse events. Therefore, it is necessary to find effective OA drugs. In recent years, novel regenerative therapies have received much attention because they can effectively promote tissue repair and regeneration. The fibroblast growth factor (FGF) signaling has been suggested to involve in cartilage homeostasis for decades. The current research shows that sprifermin/recombinant FGF18 significantly reduces the loss of cartilage thickness and volume without serious side effects, thus warrants a continued research for potential new medications of OA. This review mainly highlights the current research progress on FGFs and FGF receptors as a potential therapeutic target for OA.

Keywords: Chondrocytes, fibroblast growth factor receptor, fibroblast growth factors, joint, osteoarthritis

How to cite this article:
Chen TM, Chen YH, Sun H S, Tsai SJ. Fibroblast growth factors: Potential novel targets for regenerative therapy of osteoarthritis. Chin J Physiol 2019;62:2-10

How to cite this URL:
Chen TM, Chen YH, Sun H S, Tsai SJ. Fibroblast growth factors: Potential novel targets for regenerative therapy of osteoarthritis. Chin J Physiol [serial online] 2019 [cited 2023 Nov 30];62:2-10. Available from: https://www.cjphysiology.org/text.asp?2019/62/1/2/252834

  Introduction Top

Osteoarthritis (OA), also called degenerative arthritis, is the most common degenerative disorder in joints characterized by persistent lesion of articular cartilage, subchondral bone sclerosis, and osteophytosis.[1] Major clinical symptoms of OA patients are chronic movement-associated pain and physical disability which decrease quality and expectancy of life. Rest and analgesic treatment was suggested to alleviate these symptoms. However, OA patients feel pain as long as the joints are bearing weight, or start doing activities, which causes inconvenience and depression.[2] Currently, there are few effective therapies to prevent or delay the progression of OA.


OA is the most prevalent form of arthritis, and over 240 million people suffer worldwide.[2] Depending on the definition of subtype of OA and the specific joint(s) evaluated, the prevalence and incidence of OA vary in the different studied population.[3],[4] Using the National Health Interview Survey data of the United States, 14 million people (around 7% of adults) were estimated to have symptomatic knee OA (kOA), including more than 3 million racial/ethnic minorities.[5] Another study also showed that the incidence rates of hip symptoms and radiographic OA were 38 and 24 per 1000 person-years, respectively.[6] Four studies explored the prevalence of different joints OA in Asia.[7],[8],[9],[10] An 8% prevalence of symptomatic kOA was reported using data from the China Health and Retirement Longitudinal Study.[7] In Japan, the prevalence of hand OA (hOA) was 89.9% in men and 92.3% in women aged ≥65 years.[8] The Fifth Korean National Health and Nutrition Examination Survey also showed that 21.1% and 43.8% prevalence of kOA was estimated in men and women (aged ≥50 years), respectively.[9] The overall prevalence of kOA in India was 28.7% (aged 40–50 years).[10] In Taiwan, the prevalence of OA is about 15% reported by the Ministry of Health and Welfare of Taiwan. Over 3.5 million people suffering from OA and 20,000 people need to perform the knee replacement surgery per year in Taiwan.

In addition, OA consumes a substantial amount of health-care resources and costs worldwide.[2] Patients spend their money to visit physicians for OA. In Canada, the average direct annual cost of OA treatment increased from $577 and $811 per patient between 2003 and 2010.[11] The increased cost was primarily due to the joint replacement surgery. In addition to disturbing people's physical disability, OA may also negatively influence people's psychological health. OA patients with lower limb OA showed greater odds of developing depressive symptoms and suicidal ideation than those without the disease.[12] In the United States, the estimated average annual cost of OA health care is $140 billion.[13] In France, the medication costs of OA exceeded 1.6 billion Euros, about 1.7% of the annual expenses of their health system.[14] These reports demonstrated that OA not only causes the pain and disability of patients but also inflicts the socioeconomic burden for each country.

In the normal joint, synovial membrane around the joint produces the lubricating synovial fluid and alters the structure of bone beneath and bordering the joint as well as forming a protective cushion, named articular cartilage.[15] The cartilage surface is smooth, and the connection with underlying subchondral bone is intact which functions to reduce friction movement between the ends of long bones. Throughout their life, articular chondrocytes and subchondral bone cell obtain acute or chronic stress, strain, and load as well as respond. In the OA joint, thickening of the joint capsule, inflammation, cartilage destruction, and osteophyte formation are the major clinical observations.[16] Abnormal softening of the cartilage resulted in cartilage fragmentation (fibrillation), fibrosis, and crack formation. Articular cartilage becomes thinner during the development of degenerative possesses, and then joint bones are exposed and grinding. Osteophyte formation often occurs at the edge of the joint to replace the destructed cartilage, which also causes abnormal joint structure, bone grinding, and synovium lesion. These phenomena result in a rough surface of articular cartilage, inflammatory responses, and synovial membrane hyperplasia.[17] Over the years, these mentioned processes can culminate in noticeable loss of articular cartilage, which leads to joint dysfunction ultimately. A recent systematic review identified six clinical phenotypes: chronic pain, inflammation, cartilage destruction, minimal joint, osteophyte formation, and mechanical overload.[17]

  Risk Factors Top

The risk factors of OA were divided into person-level factors and joint-level factors.[3] Person-level factors include age, gender, obesity, diet, and genetics. Joint-level factors include injury and overloading of the joints. Here, we focus on person-level factors.

Age and gender

Age is the main risk factor of OA.[18] The prevalence increases with age which occurring after the age of 40–50 years.[18] The mechanism is multifactorial, which includes muscle weakening, oxidative stress, cartilage thinning, and proprioception loss.[19] Gender is also a well-known risk factor for OA. The disease is more common in women than men.[19] Studies showed that the level of sex hormones play certain roles in the development of OA, however, these results are still under debating.[20]

Obesity and metabolic syndrome

The definition of obesity is body mass index (BMI) >30 kg/m2, which has been shown as a risk factor for kOA with a dose-response relationship. Every 5-unit increase in BMI, the risk of kOA increases for 35%.[18] Silverwood et al. estimated that 24.6% of cases were overweight or obesity in newly diagnosed patients.[18] Conversely, weight loss has been constantly associated with improved OA symptoms and slower knee cartilage degeneration. Christensen et al. showed that the risk of developing kOA decreased by 50% after 5 kg weight reduction.[21] Preclinical and clinical observation reported that increased cholesterol levels in the elder population showed a positive association with OA.[21] Frey et al. also demonstrated that hyperlipidemia is an independent risk factor for new-onset hOA.[22]


As Vitamin D plays a key role in cartilage and bone metabolism, and low level of Vitamin D intake has been suggested to increase OA risk. Previous studies showed that sufficient Vitamin D level keeps the cartilage structure intact and reduces the effusion synovitis.[23] However, another study showed that sufficient Vitamin D supplement did not decrease the progression of joint space narrowing. Therefore, the role of Vitamin D on OA prevention is still under debating.[24] Other specific diets also showed to be associated with OA progression. For instance, high fiber intake has been shown to be associated with lower risk of kOA.[25]

Genetic factor

OA has a strong genetic component. Genetic factors are determined to contribute approximately 30%–65% of the risk for OA development.[3],[4] Review articles summarized key findings from many association studies on OA.[26] So far, many OA susceptibility loci were identified by a genome-wide associated scan studies. Among these loci, nuclear receptor coactivator 3, sulfatase 2, carbohydrate sulfotransferase 11, histone H3 lysine 79 methyltransferase, runt-related transcription factor 2 (RUNX2), and insulin-like growth factor-binding protein 3 have been suggested to consider as repositories of OA genetic risk.[27] In addition, other candidate genes also have been explored to associate with OA. For instance, SNP rs11718863 in the collagen type VI alpha 4 pseudogene 1 (COL6A4P1, also known as DVWA) is associated with OA risk in Asians.[28] SNP rs4238326 in aldehyde dehydrogenase 1 family member A2 is associated with kOA susceptibility in Chinese population.[29]

Current treatment options

Despite causing remarkable socioeconomic liability and individual distress, currently, there are no effective treatment options for OA. The main approaches of OA treatment involve non-pharmacological, pharmacological, and surgical procedures to reduce pain and improve physical activity of joints.[30] Non-pharmacological approaches of OA treatment include strengthening the muscles by exercises, weight loss, and massage therapies.[31] The present pharmacological agents simply provide indicative pain relief; include (i) acetaminophen; (ii) nonsteroidal anti-inflammatory agents; (iii) opioid analgesics; (iv) serotonin–norepinephrine reuptake inhibitors; and (v) intra-articular injections.[31] OA patients with poor responses to conventional therapies are eventually treated with surgical procedures to repair the surface of cartilage, implantation of artificial joint structures (arthroplasty) or total joint replacement, which helps them to relief from arthritic pain and improve the activity.[17] Among all joints, the knee is the most common site for OA. Statistically, 700,000 total knee arthroplasties were performed in the United States in 2010, which nearly 50% of OA patients.[32]

  Molecular Mechanism of Osteoarthritis Top

Normally, the traditional pharmacologic therapy only shows efficacy in pain relief. However, these medications cannot delay the progression of OA and are frequently associated with adverse events.[31] Therefore, more information of OA may allow us to develop new therapeutic targets to prevent new disease onset and decrease disease progression. Emerging regenerative therapy on the articular cartilage has gained much attention during recent years. Incomplete understanding of disease mechanism might be the reason of no effective OA treatment options. Currently, the information on the molecular regulation and pathological mechanism of OA mainly comes from two major study strategies. One is the observation of OA similar phenotype by genetic animal model and the other is surgical animal model for overloading or instability of the joint. Thus far, the widely used animal models for OA pathophysiological studies are age-associated (spontaneous) and instability-induced through joint surgery. Among the instability-induced joint surgery, anterior cruciate ligament transection and destabilization of the medial meniscus (DMM) are commonly used surgical techniques in rodents, which mimic human posttraumatic OA, and structural similarity. In the past few years, some OA relative candidate pathways and cellular processes that have been identified form these animal models, include growth factor signaling, inflammation, nociceptive signaling, and chondrocyte autophagy.[30]

OA is associated with the irreversible degeneration of articular cartilage. In this regard, the balance of anabolic and catabolic process of endochondral ossification is vital for the development of OA.[33] In these processes, the proliferation and differentiation of chondrocytes are tightly controlled by circulating systemic hormones and many growth factor signaling pathways. The level of key downstream targets, such as expression of collagen X (COL10A1) and matrix metalloproteinase-13 (MMP13), is then modulated in articular cartilage chondrocytes during endochondral ossification.[34] Prior investigations indicated that aggrecan cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 5 (ADAMTS5) is critical for the breakage of cartilage matrix in OA.[35] Syndecan-4, a transmembrane heparan sulfate proteoglycans, interact with a variety of extracellular matrix (ECM) molecules and growth factors as well as cytokines is specifically enhanced in collagen X-producing chondrocytes both in human OA and mice models.[35] ADAMTS5 activity was dramatically attenuated in syndecan-4-deficient mice, and syndecan-4-specific antibody treated wild mice.[35] Based on these studies, the ECM-related molecules, such as collagen X, MMP13, and ADAMTS5, are considered as biomarkers of OA progresses.

  Fibroblast Growth Factor Receptor Top

Various pathways have been suggested to involve in cartilage development or joint formation, which link to OA pathogenesis and could theoretically serve as therapeutic targets.[36] Among these signaling factors, fibroblast growth factors (FGFs) particularly attract more attention by several new studies. Therefore, we mainly focus on the development of FGFs on OA treatment in this review.

An FGF receptor (FGFR) commonly comprises an extracellular ligand-binding domain, a transmembrane region, and an intracellular divided tyrosine kinase domain.[37] FGFs bind to the extracellular domain of FGFRs and induce the phosphorylation of tyrosine residues of FGFRs. Alternative splicing variants of FGFRs (designated as IIIa, IIIb, and IIIc) have tissue-specific expression patterns and distinct ligand binding properties of their ligands.[37] Activated FGFRs recruit target proteins to their cytoplasmic tail, and activate downstream signaling pathways by phosphorylation, including Ras-mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, phospholipase C, and protein kinase C pathways.[38] Downstream targets of FGFRs also include several signaling adaptors such as GAB2-associated binding protein 1,[39] SH2 domain containing adaptor protein B,[40] and SH2 domain containing transforming protein 1.[41] Moreover, the FGFR pathway plays essential roles in skeletal development.[42] All FGFR subtypes (FGFR1–4) are expressed in human adult articular chondrocytes. Among them, the level of FGFR1 and FGFR3 were significantly higher than FGFR2 and FGFR4.[43],[44] Notably, the level of FGFR1 expression is increased with a concomitant suppression of FGFR3 in human OA cells,[43],[45] suggesting a pathological link of FGFR1 and an anabolic role of FGFR3 signaling in OA [Figure 1].
Figure 1: Schematic model of fibroblast growth factor receptor 1 and fibroblast growth factor receptor 3 signaling pathways in articular cartilage. (a) Fibroblast growth factor 2 binds to fibroblast growth factor receptor 1/ß-klotho and actives Ras-Raf-MEK1/2-extracellular-signal-regulated kinase1/2 axis, which triggers transcription factors, such as Elk-1 and RUNX2, to upregulate downstream genes and stimulate the catabolic effect in articular cartilage. (b) Fibroblast growth factor 9 or 18 binds to fibroblast growth factor receptor 3/ß-klotho and activates Akt and other mitogen-activated protein kinase pathways, which triggers other transcription factors, such as forkhead box (FOX), to stimulate the anabolic effect in articular cartilage

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Fibroblast growth factor receptor 1

FGFR1 is highly expressed in human knee chondrocytes.[43] Ellman et al. showed that FGF2 activates catabolic events and inhibition of proteoglycan synthesis by FGFR1 signaling in human articular chondrocytes through the activation of multiple transcription factors, such as RUNX2 and Elk-1.[46] FGF2-mediated FGFR1 activation also leads to chondrocyte hypertrophy, which is considered as a key event in the initiation and progression of articular cartilage degeneration. The level of FGFR1 is also upregulated compared to FGFR3 in degenerative cartilage, thus suggesting FGFR1 is the predominant FGF pathway in cartilage degeneration.[45] Moreover, inactivation of FGFR1 signaling by using fgfr1 conditional knockout mice attenuated cartilage degeneration with reduction of MMP13 expression.[47] Recently, Wang et al. reported that conditional deletion of Fgfr1 delayed OA progression in temporomandibular joint OA model and inactivation of FGFR1 signaling may promote autophagic activity.[48] These results suggest FGFR1 has catabolic effects in human adult articular cartilage by inhibition of ECM production, and upregulation of matrix-degrading enzyme production.

Fibroblast growth factor receptor 3

Many lines of evidence point out that FGF-FGFR3 axis is a vital signaling pathway for OA. Mutations in human FGFR3 or knockout of Fgfr3 in mice cause skeletal dysplasias [49] demonstrating that FGFR3 is important in skeletal development and indicating FGFR3 may play an essential role in the maintenance of articular cartilage. FGFR3 is abundantly expressed in healthy articular chondrocytes, however, is reduced in OA patients.[44] Conventional FGFR3 knockout (FGFR3-/-) mice develop early-onset arthritis and exhibit abnormal skeletal development.[50] Tang et al. showed that conditional Fgfr3 deletion upregulates biomarkers (MMP13 and collagen X) of cartilage degeneration in mice and intensify DMM-induced cartilage degeneration. Conversely, chondrocyte-specific FGFR3 activation reduced cartilage degeneration induced by DMM-treated and age-induced OA mice.[51]

FGF2, 9 and 18 has been proposed to trigger anabolic activities through FGFR3 signaling in articular cartilage.[52],[53] Among them, FGF9 and 18 have high specificity for FGFR3 signals in articular cartilage. FGFR3 signaling appears to activate a different set of downstream transcription factors that lead to chondroprotective outcomes. As opposed to the FGFR1 signaling, the activation of FGFR3 exerts anabolic effects in articular cartilage, which reflected by increased cell-associated matrix formation and promotion of cell viability.[54] On the other hand, FGFR3 plays a dominant anabolic role after ligand binding by FGF9 and 18, demonstrated by potent stimulation of cartilage repair. These findings reveal FGFR3 is a chondroprotective factor in mouse joints and strongly suggest that FGFR3 pathway could be a novel treatment targets for OA.

  Fibroblast Growth Factors Top

FGFs are secreted proteins that trigger signals through activation of their cognate receptors (FGFRs). To date, 24 members of the FGF family (FGF1–24, sharing with 13%–71% amino acid identity) have been found in organism ranging from nematodes to human.[37] Most of the FGFs share a conversed 120 amino-acid core region which consists of 12 antiparallel-β-strands.[55] FGFs are abundantly expressed in embryonic development with different patterns and regulate a plethora of developmental processes.[37] FGF/FGFR signaling has also been reported to play vital roles in maintaining homeostasis of chondrocyte degeneration and repair.[46] In the FGF family, FGF1, 2, 8, 9, and 18 are shown to play important roles in OA disease progresses as summarized below.

Fibroblast growth factor 1

FGF1 is a classical member of the FGF family and expressed in chondrocytes isolated from osteoarthritic patients.[56] FGF1 also binds to connective tissue growth factor (CTGF), which is increased in cultured chondrocytes in OA mice model.[57] However, the pathophysiological role of FGF1 in cartilage tissue is still unclear. Recently, remarked repression of MMP13 and CTGF was observed in FGF1-treated human chondrocytes, suggesting its catabolic effects on cartilage.[58] Notable, a positive feedback of FGF1 expression was observed both in chondrocytes and in the articular cartilage of a rat OA model.[58]

Fibroblast growth factor 2

FGF2 is highly expressed in the synovial fluid of OA patients, which is released from damaged cartilage and subsequently activates the extracellular-signal-regulated kinase signaling pathway.[59] FGF2 causes proteoglycan reduction in cartilage explants and inhibits long-term proteoglycan accretion in articular chondrocytes through RUNX2 and ADAMTS5 activation.[43],[45] The level of FGF2 positively correlates with MMP1 and MMP13, but negatively correlates with aggrecan and collagen II in human OA chondrocytes,[60] which suggests FGF2 might induce catabolic effects on human OA cartilage. Furthermore, treatment with AZD4547 and NVP-BGJ398 (FGF receptor antagonists) downregulated the expression of MMP1 and MMP13 in human OA chondrocyte, representing a promising beneficial effect on the balance of catabolic and anabolic activity of OA cartilage.[60] Remarkably, the role of FGF2 seems to contradict in murine cartilage. Ablation of FGF2 leads to speeded up age and surgical-induced OA development in mice; however, it can be rescued by recombinant FGF2 treatment.[61] These results suggest FGF2 plays a chondroprotective role and may have the potential as a cartilage repair agents in murine OA.[62] Such discrepancies raise the question of whether the function of FGF2 in articular cartilage is fundamentally different between species.

Fibroblast growth factor 8

FGF8 is isolated as an androgen-induced growth factor and involved in limb morphogenesis and chondrogenic development.[63] The expression level of FGF8 is induced in the hyperplastic synovial cells and fibroblasts in OA rabbit model, whereas little expression is detected in the normal rabbit.[64] In cultured chondrocytes, FGF8 induced the level of MMP3 and prostaglandin E2, which causes degradation of the ECM. The injection of anti-FGF8 antibody into rat knee joints suppresses the FGF8-induced ECM degradation,[64] suggesting FGF8 may play roles in the balance of catabolic and anabolic activity of cartilage in OA patients.

Fibroblast growth factor 9

FGF9 is originally isolated from the conditional medium of human glioma cell line (NMCG-1) and functions as a trophic factor of glial cells.[65] FGF9 is broadly expressed in different tissues such as apical ectodermal ridge, perichondrium/periosteum, chondrocytes of the growth plate, and primary spongiosa.[66] Fgf9 knockout (Fgf9-/-) mice revealed a lethality at the neonatal stage resulting from malformations of the lung and causing male-to-female sex reversal.[55] Fgf9-/- mice also exhibit disproportionate shortening of the proximal skeletal elements, but the limb bud development and mesenchymal condensation are normal.[66] Likewise, transgenic mice constitutively expressed Fgf9 in chondrocytes (Col2a1-Fgf9), display dwarfism, short limb, and vertebral defect due to the reduced proliferation and terminal differentiation of chondrocytes.[67] Furthermore, missense mutation in FGF9 (S99N) has been reported to show the elbow-knee synostosis, premature fusion of cranial sutures in mice, and multiple synostosis syndrome in humans,[68] implying that ectopic FGF9 inhibits terminal differentiation of chondrocytes which resulting in the loss of the joint cavity. Based on these notions, observation from Fgf9 knockout and transgenic mice suggest a vital role of FGF9 on skeletogenesis and joint formation.

Recently, Dai et al. demonstrated that exogenous FGF9 is able to simultaneously induce the chondrogenesis of dental pulp stem cells and partially inhibits their ossification in engineered cartilage.[69] Zhou et al. showed that FGF9 is significantly downregulated in articular cartilage of OA patients compared to healthy articular cartilage. Meanwhile, intra-articular injection of recombinant FGF9 reduces articular cartilage degeneration in DMM-treated mice. The biomarkers of chondrocyte hypertrophy, such as collagen X and MMP13 are also down-regulated by FGF9 injection.[70] These results suggest FGF9 has a protective effect of damaged articular cartilage during OA development, which partially through delaying hypertrophy in both humans and mice. However, FGF9 treatment aggravates osteophyte formation, which presents an adverse effect and is associated with chronic pain and loss of function in joints. Therefore, further study focusing on optimizing the dosages of FGF9 for better outcomes needs to be taken.

Fibroblast growth factor 18

FGF18 plays a crucial role in skeletal growth and development and has been reported to have significant anabolic effects on cartilage as well as articular cartilage repair.[71] Local overexpression of fgf18 by adenovirus induces the expression of type II collagen, chondrocyte proliferation, and formation of auricular cartilage. Dramatic enlargement of bronchial cartilage is observed in fgf18 transgenic mice.[72] Moore et al. demonstrated that intra-articular injection of FGF18 induces cartilage repair in OA-treated rat. A series of injection of FGF18 induces dose-dependent increases in cartilage thickness in surgical OA rat model in vivo, which results in significant reductions in cartilage degeneration.[52] In addition, FGF18 suppresses noggin expression and facilitates the chondrogenic activity in human cartilage. Li et al. reported that noggin gene expression is increased in a dose-dependent manner after FGF2 treatment. Therefore, the balance of noggin signaling mediated by FGF2 and FGF18 may serve as a potential mechanism for cartilage homeostasis.[73]

Weekly injection of recombinant human FGF18 for 3 weeks prevents cartilage degeneration and stimulates the repair of damaged cartilage in a surgical rat OA model.[74] Due to the success of animal experiments, the clinical study of FGF18 recombinant protein in OA treatment is undergoing. The first clinical trial of sprifermin revealed no serious safety concerns.[75] A following study demonstrated that sprifermin treatment significantly reduced the loss of cartilage thickness and volume as well as the joint space width narrowing without serious adverse events in kOA patients.[76] Recently, primary data from the currently ongoing 5-year phase II study of sprifermin showed a dose-dependent increase in total femorotibial joint cartilage thickness with an acceptable safety profile.[77] However, further basic and clinical studies should be accomplished to completely examine this novel OA biologic drug.

  Other Signaling Pathways in Osteoarthritis Pathogenesis Top

Wnt and transforming growth factor-β pathways

The transforming growth factor (TGF) signaling pathway is a key factor in OA development. Significantly, reduced cartilage damage was shown in TGF-α null mice after DMM-treatment.[78] Xie et al. reported administration of TGF-β neutralizing antibody prevented articular cartilage degeneration in ACLT-treated mice.[79] Moreover, specific deletion of Tgfbr2 showed a protective effect on articular cartilage degeneration in DMM-treated mice.[80] In addition, the epidermal growth factor receptor (EGFR) signaling pathway also been shown to be increased in the knee joints of DMM-treated mice. Heparin-binding epidermal growth factor-like growth factor is found to contribute to the catabolic-anabolic imbalance of OA cartilage tissue.[81] Cartilage-specific deletion of mitogen-inducible gene-6 (an inhibitor of EGFR signaling), in mice, leads to OA-like disorder in multiple synovial joints.[82]

Various signaling molecules also involve in skeleton development, such as wingless-type MMTV integration site family members (Wnt), bone morphogenetic protein signaling cascades, and hypoxia-inducible factor (HIF).[30] The inhibition of β-catenin signaling results in cartilage degradation and OA-like phenotype in mice.[83] Similarly, the administration of antagonists of Wnt also showed protective effects against articular cartilage degradation and OA.[83] In addition to regulating OA cartilage matrix, HIF-2α transcriptionally regulates endochondral ossification during skeletal growth and OA development.[84] HIF-2α directly binds to hypoxia response element to activate the expression in chondrocytes of genes which play a vital role during OA development such as matrix metalloproteinase (MMP1, MMP3, MMP9, MMP12, and MMP13), aggrecanase-1, nitric oxide synthase-2, cyclooxygenase-2, vascular endothelial growth factor A, and COL10A1.[85]

Inflammation mediators

Traditional proinflammatory mediators such as interleukin 1β (IL-1β), chemokines, and toll-like receptor 2, 4 signaling have been implicated in activating OA inflammation pathophysiology.[86] These proinflammatory mediators induce cytokine production and perpetuation of inflammatory responses and catabolic activity in the joint. Superoxide dismutase 2 is an enzyme to reduce reactive oxygen species, another type of inflammatory mediators, in OA joints and its downregulation has been implicated in OA pathology.[87] Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor that regulates the expression of antioxidant proteins, and ablation of Nrf2 resulted in increased cartilage damage in DMM-treated mice.[88]

IL-1 is the predominant pro-inflammatory cytokines involved in OA progression.[89] IL-1 and other pro-inflammatory cytokines can promote the MMP degradation and accelerate the cartilage destruction in OA.[90] Although the mechanism between proinflammatory factors and FGFs signaling are not clear, evidence showed that FGFs signaling can crosstalk to IL-1 pathway and reduced their catabolic effect in OA. For instance, FGF9 treatment significantly enhanced the collagen II expression, which protected IL-1β-induced degradation of adult human articular cartilage.[70] Intra-articular injection of a novel non-ATP-competitive FGFR1 inhibitor, G141, resulted in a marked reduction of the mRNA levels of IL-1β and attenuated the cartilage destruction in DMM-induced mice.[91] Thus suggesting both FGF analogs for FGFR3 signaling and FGFR1 inhibitors may attenuate the phenotype of OA by reducing the catabolic effect of pro-inflammatory cytokines.

Nociceptive signaling

The main reason for OA patients to search for medical care is joint pain. Nerve growth factor and tropomyosin receptor kinase A (TrkA) are involved in the development of nociceptive sensory neurons in both chondrocytes and fibroblast-like synoviocytes, which appear to have a role in pain sensitization in OA.[92] Oral delivery of TrkA's inhibitor demonstrated anti-nociceptive effects of pain-like behaviors without enhanced cartilage damage.[93] In addition, clinical trials with anti-nerve growth factor monoclonal antibodies in OA patients also showed results supporting anti-nociceptive neurons could be a potential therapeutic strategy of OA.[94]

Chondrocyte autophagy

Autophagy is a protective eukaryotic process for cells from conditions of cellular stress, such as oxidative stress and nutrient withdrawal, by recycling damaged cytoplasmic materials and maintaining energy homeostasis. Abnormal autophagy progresses occur in a variety of disease states, such as OA.[95] Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that functions as a key suppressor of autophagy. Chondrocyte protective effects were shown in DMM-treated mice with cartilage-specific deletion of mTOR, which strongly supports the role of autophagy in OA.[95] Peroxisome proliferator-activated receptor gamma, another mediator of mTOR signaling, also showed an important role in OA mice model.[96] Similarly, mice with cartilage-specific deletion of Atg5, a protein vital for autophagy processes, develop an aging-associated OA.[97]

  Conclusions Top

The current clinical treatment strategies for OA fail to interfere with disease progression, which may result from the poor regenerative ability of cartilage tissue. Recent studies began to search the potential biological agents to slow or reverse cartilage degradation. FGFR1 antagonists and FGFR3 antagonists reveal a promising result to prevent cartilage degeneration or promote cartilage regeneration in many studies, suggesting a potential therapeutic strategy in the future. Members of the FGF family may function as contributing factors in cartilage homeostasis. FGF2 and 8 have been found to induce catabolic effects in human cartilage, while FGF9 and 18 demonstrate anabolic effects. Due to the level of FGFR3 was gradually decreased in chondrocytes during OA development.[98] Thus, early administration of exogenous FGFs, such as FGF9 and FGF18, to activate FGFR3 signaling may have better effects for OA treatment. Otherwise, using nanoscaffolds to mimic the extracellular matrix and combine with growth factors treatment, human bone marrow mesenchymal stem cells have been successfully differentiated into chondrocytes.[53] Therefore, FGFs may also have the potential to apply to the tissue engineering for OA treatment [Figure 2].
Figure 2: Schematic diagram illustrating the current application of fibroblast growth factors for osteoarthritis treatment. Recombinant human fibroblast growth factor 9 and 18 (rhFGF9, FGF18) act as fibroblast growth factor receptor 3 antagonists to induce the anabolic effects of damaged cartilage; fibroblast growth factor 2 and 8 antibody act as fibroblast growth factor receptor 1 antagonists to induce the catabolic effects of damaged cartilage. Both of them can be used to keep the homeostasis of cartilage regeneration. Furthermore, bone marrow mesenchymal stem cells can successfully differentiate into chondrocytes using nanoscaffolds or sequential fibroblast growth factor signal stimulation, and then be transplanted into damaged cartilage

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Financial support and sponsorship

This study was supported by grants from the Ministry of Science and Technology in Taiwan (MOST 105-2628-B-022-001-MY3 and MOST 106-2320-B-006-072-MY3).

Conflicts of interest

There are no conflicts of interest.

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