Fibroblast growth factor receptor (FGFR)1 has
recently emerged as a critical regulator of bone remodeling in RA
pathogenesis (13-20). FGFR1 is widely expressed in bone,
cartilage and synovial tissue, where it regulates skeletal
development, remodeling and inflammatory responses (21-26). Dysregulation of FGFR1 signaling
is implicated in various pathological conditions, including RA,
where excessive activation contributes to synovial hyperplasia,
cartilage degradation and bone erosion (14,27-29). FGFR1, activated by FGFs, signals
through key downstream effectors including MAPK, PI3K/AKT and
phospholipase Cγ (PLCγ) (30,31). Dysregulated FGFR1 signaling has
been implicated in the aberrant bone remodeling central to RA
(32).
The present review aimed to summarize the structural
biology of FGFR1, its multifaceted roles in bone homeostasis and
its pathological contributions to RA-associated joint damage, as
well as FGFR1 as a therapeutic target and the translational
potential of FGFR1-modulating strategies for RA treatment. The
present study aimed to provide a framework for developing targeted
interventions to prevent structural progression in RA and
associated osteolytic disorders.
FGFRs are widely distributed, highly conserved
transmembrane tyrosine kinase (TK) receptors (33). FGFR adopts a bilobal kinase
architecture defined by an N- and a C-terminal lobe. These two
structural domains form a catalytic groove that accommodates both
ATP and peptide substrates. This serves an important role in the
receptor kinase activity and regulation (34). FGFR1 is one of four main members
of the FGFR family, which includes FGFR1, FGFR2, FGFR3 and FGFR4.
Located at 8p11.23 and comprising 68,620 bases (35). FGFR1 is a cell surface TK
receptor. FGFR1 comprises a triad of extracellular Ig-like modules
(D1-D3), followed by a transmembrane α-helix and a pair of
cytoplasmic TK units, TK1 and TK2. Numerous junctional regions are
interspersed between these domains, playing a crucial role in
maintaining the structural integrity of FGFR1 (36). Notably, the linkage between D1
and D2 is facilitated by a short sequence consisting of 7-8 amino
acids. Composed of a stretch rich in acidic and serine residues,
the acid box cooperates with Ig-like domain 1 to impose an
autoinhibitory constraint on FGFR (37,38) (Fig. 1). D2 has a heparan sulfate
(HS)-binding site, consisting of a conserved positively charged
region (39). The D2 and the D3
region are key for ligand binding and specificity (40). FGFR1-3 undergo alternative
splicing, generating b and c isoforms that modulate ligand
specificity through structural alterations in the ligand-binding
region (41-43). This regulatory mechanism is
achieved by modifying the primary amino acid sequence within the
C-terminal half of immunoglobulin-like domain D3, a key determinant
of ligand-receptor interactions. Such isoform-specific variations
in the extracellular domain enable differential recognition of
FGFs, thereby regulating signaling responses in a tissue- and
context-dependent manner (44,45). A fifth non-TK FGFR, FGFR5, is
homologous to FGFR1-4 in the extracellular ligand-binding domain,
but does not have an intracellular TK domain. FGFR5 was first
discovered in human cartilage (46). The four FGFRs exert protein TK
activity in the cell, while FGFR5 has a short non-enzymatic
intracellular element of 105 amino acids (47). FGFR5 was originally hypothesized
to function as a non-signaling decoy receptor, exerting an
inhibitory effect on the classical FGFR signaling pathway (48). This regulatory role is
hypothesized to be mediated through competitive binding to ligands,
thereby decreasing their availability for interaction with
canonical FGFRs and modulating downstream signaling responses
(49,50). FGFR5 not only serves as a
negative regulator but also actively engages in the canonical FGFR
signaling pathway (48,51-53). This dual role includes mediating
key biological functions such as the promotion of cell
differentiation, suggesting a more complex regulatory mechanism.
These findings highlight the context-dependent nature of FGFR5
activity, where its interaction with canonical FGFR components can
inhibit or enhance downstream signaling outcomes depending on cell
context and ligand availability. The expression of FGFR5 increases
with FGFR2 and FGFR1 when mesenchymal cells differentiate into
osteoblasts or adipocytes (54).
In β cells of the pancreas, FGFR5 interacts with SHP-1 and promotes
ERK1/2 signaling (55). FGFR5 is
inflammation-inducible and serves as a FGFR1 coreceptor to enhance
survival signaling (52).
Deletion of FGFR1 in osteocytes leads to an increase in trabecular
bone mass and cortical bone thickness, which is associated with
increased bone formation and impaired bone resorption (56). FGFR1 can regulate bone mass in
osteocytes by modulating Wnt/β-catenin signaling (35). This provides genetic evidence
that FGFR1 serves a crucial role in bone cells during bone
remodeling and suggests FGFR1 may be a potential therapeutic target
for preventing bone loss (35).
Activation of the FGFR1 signaling pathway is implicated in various
chronic inflammatory diseases, including RA (14,36,52,57).
FGFR1-3 use alternative splicing to generate
isoforms with distinct ligand-binding properties, exhibiting
lineage-specific expression patterns in epithelial and mesenchymal
tissues (58). This
splicing-mediated diversification enables context-dependent
modulation of receptor-ligand interactions, contributing to
tissue-specific signaling outcomes (48). FGFRb variants are predominantly
expressed in epithelial lineages and interact with
mesenchymal-derived FGFs (FGF7/10), reflecting a paracrine
signaling paradigm (59).
Conversely, FGFRc isoforms localize to mesenchymal compartments and
bind FGF ligands produced in both epithelial and mesenchymal
tissues, enabling autocrine/paracrine signaling flexibility
(60,61). This splicing-mediated receptor
diversification creates tissue-specific receptor-ligand interfaces
that modulate developmental and homeostatic processes through
differential ligand availability and binding kinetics.
The biological activity of FGF is enhanced by
interactions with HS and other sulphated glycosaminoglycans
(38,62). The protein class present on the
cell surface and extracellular matrix is primarily composed of HS
proteoglycan (HSPG), which includes HS covalently bound to a
protein core. HSPG consists of membrane-spanning proteins on the
cell surface, cell surface proteins anchored by
glycosylphosphatidylinositol and diffusible protein components of
the extracellular matrix such as basement membrane and agrin
(38). Cell surface HSPGs and
extracellular matrix regulate FGF diffusion dynamics in tissue,
acting as cofactors stabilizing FGF-FGFR heterodimer complexes
through electrostatic interactions, thereby enhancing ligand
receptor affinity and intensifying downstream receptor activation
cascades (63-65). Endocrine FGF differs from
classical FGF in that it requires protein cofactors to promote
receptor binding and activation. Members of the Klotho family
fulfil this role, as evidenced by phenotypic similarities observed
in αKlotho and FGF23 knockout (KO) mice (66-68).
The binding of FGF ligands to FGFRs induces
dimerization and juxtaposition of the TK domains, thereby
initiating the sequential transphosphorylation of at least six
tyrosine residues (38,69,70). Activation of the FGFR TK domain
induces direct phosphorylation of FGFR substrate 2α (FRS2α) docking
binding proteins and promotes the recruitment of downstream
signaling molecules, including PLCγ, STAT1, STAT3 and STAT5,
through the formation of receptor-substrate complexes (38). In fibroblasts, FGF ligand
stimulation triggers FGFR3 to activate STAT (71,72). Phosphorylated FRS2α activates the
MAPK pathway through Son of sevenless. Additionally, phosphorylated
FRS2α binds growth factor receptor-bound protein 2 (GRB2), which
subsequently recruits GRB2-associated binder 1 to trigger the
PI3K/AKT signaling pathway (73,74). Downstream from RAS and PI3K, FGFs
activate several distinct MAPKs, including ERK1/2, JNK and p38
(75-79). The binding of v-crk sarcoma virus
CT10 oncogene homolog-like to the activated FGFR enhances the
phosphorylation of FRS2α, as well as the MAPK pathway signaling and
the activation of ERK1/2 (80).
FGFR intracellular signaling cascades are subject to
inhibitory regulation mediated by molecules such as GRB2. GRB2,
which binds to FRS2α, forms a complex with the casitas B-lineage
lymphoma (CBL) E3 ligase, which transfers ubiquitin molecules to
FGFR and FRS2α, leading to their polyubiquitination (81). The ubiquitinated receptor and
adaptor proteins are targeted by lysosomes or proteasomes for
degradation, effectively shutting down ongoing signaling and
achieving negative feedback inhibition (81). Sprouty proteins, which interact
with GRB2 to suppress downstream MAPK and PI3K pathway activation
(82,83). In the downstream region, similar
expression to fibroblast growth factor antagonizes the MAPK pathway
through its interaction with MEK (84), while dual-specificity phosphatase
6 suppresses MAPK signaling through the dephosphorylation of ERK1/2
(85). CBL E3 ligase has been
shown to inhibit FGFR signaling by forming a triple complex with
phosphorylated FRS2 and GRB2, where it promotes ubiquitination and
degradation of FGFR and FRS2 (86). CBL interacts with PI3K, resulting
in its ubiquitination and degradation (87). The GRB14 adapter protein binds
phosphorylated FGFR of Tyr766, thereby interfering with
phosphorylation and activation of PLCγ (88).
As aforementioned, FGFR1 is a TK cell surface
receptor, the expression of which is primarily observed in the
extracellular matrix and smooth muscle tissue, which constitutes a
notable component of cartilage tissue. RA primarily affects
cartilage tissue, leading to bone destruction (35,56,58,89). Consequently, FGFR1 may serve a
pivotal function in the progression of RA. In vitro,
attenuation of the FGFR1 signaling pathway may lead to attenuation
of bone decay and beneficial therapeutic effects in rat models of
arthritis (14,90). The immunoglobulin-cell sII and
III domains of FGFR1, together with the interdomain hinge regions,
serve a key role in the regulation of FGF ligand binding
specificity (91). The acidic
amino acid motif AB, located within the interdomain region between
extracellular immunoglobulin-like domains I and II of FGFR1,
demonstrates an inhibitory effect on FGFR ligand-receptor
interactions when acting in concert with domain I (92). The intracellular TK domain of
FGFR1 demonstrates constitutive TK activity. In the absence of FGF,
the receptor exists as a monomeric unit with the TK domain
maintained in a phosphorylated state. Following FGF engagement,
receptor dimerization facilitates the formation of a functional
2FGF:2FGFR1 complex, leading to kinase activation and
trans-phosphorylation events. This results in full TK activation
and subsequent downstream signal transduction cascades (59,93-95).
Following exposure to FGFs and heparin/klotho, FGFR1
kinases undergo dimerization in the active
aspartate-phenylalanine-glycine motif-aspartate-in conformation
(DFG-Asp-in) conformation, a process mediated by co-receptor
interactions that stabilize the signaling complex and promote
kinase activation (96). FGF
demonstrates preferential binding to the extracellular domains of
FGFR, with a marked affinity for the D2 and D3 immunoglobulin-like
domains and their intervening interdomain linker regions. This
binding stabilizes the FGF-FGFR-HS complex and promotes receptor
dimerization (97). Upon
receptor dimerization, the FGFR kinase domain undergoes
conformational reorganization, transitioning from an Upon receptor
dimerization, the FGFR kinase domain shifts from the autoinhibitory
DFG-out conformation to the catalytically active DFG-in
conformation (97). This
structural rearrangement facilitates ATP-binding pocket alignment
and activation loop stabilization, enabling kinase activation and
downstream signaling initiation. In its active DFG-in conformation,
the FGFR kinase domain DFG motif aspartate residue orients toward
the catalytic site, enabling ATP coordination and substrate
phosphorylation (97,98). Following FGF and heparin/klotho
engagement, FGFR1 kinases assemble into active DFG-in
conformational dimers, a process stabilized by co-receptor
interactions. Trans-phosphorylation of tyrosine residues within the
activation loop amplifies kinase catalytic efficiency through
allosteric modulation of the catalytic site (99,100). The intramolecular regulatory
element within the FGFR kinase domain, composed of the conserved
never in mitosis gene A-related kinase triplet, undergoes
conformational disengagement. This structural rearrangement
disrupts the hydrogen-bonding network that stabilizes the
autoinhibited state, thereby enabling the kinase domain to adopt a
catalytically competent conformation (96). In this active conformation, the
activated kinases trigger downstream signaling cascades through the
recruitment of cytoplasmic adaptor proteins, thereby activating key
intracellular pathways including RAS/MAPK, PI3K/AKT, PLCγ and STAT
signaling. This process involves the formation of multi-protein
complexes that transduce extracellular signals to nuclear
effectors, modulating cell responses such as proliferation,
differentiation and survival (38) (Fig. 2).
FGFR1 signaling, through its downstream effectors
including RAS/MAPK and PI3K/AKT pathways, serves a crucial role in
numerous physiological processes. During embryogenesis, FGFR1 plays
a pivotal role in regulating essential cell behaviors, including
proliferation, differentiation and migration, which are fundamental
for the proper formation of tissue and organs (101-103). FGFR-mediated signaling
coordinates the morphogenesis of neural, skeletal and
cardiovascular systems, ensuring precise spatiotemporal integration
and functional maturation of developing organ structures (104-106). FGFR1 exerts key functions in
regulating developmental processes and sustaining metabolic
homeostasis during infancy and postnatal maturation. Its signaling
is key for driving tissue expansion, orchestrating organogenesis
and modulating nutrient utilization pathways to ensure proper
growth trajectories and metabolic equilibrium (107). FGFR1 modulates adipogenic
differentiation and governs glucose homeostasis alongside lipid
metabolic pathways, thereby serving as a key regulator of systemic
energy balance (108). This
multifaceted role positions FGFR1 signaling at the nexus of
metabolic regulation, integrating nutrient sensing with cell energy
utilization (109). FGFR1
serves a pivotal role in metabolic regulation, which is key for the
adaptation of the body to fluctuating nutritional and energy
demands throughout the growth and maturation process (110). FGFR1 signaling coordinates
tissue repair and regeneration in adults via stem cell activation
modulation, angiogenesis promotion and extracellular matrix
remodeling regulation (111,112). FGFR1 serves a pivotal role in
orchestrating cellular injury responses (113). It boosts the proliferation and
migration of stromal fibroblasts, vascular endothelial cells, and
other typical reparative cells including mesenchymal stem cells and
pericytes, all of which are key for tissue regeneration (114,115). This signaling axis modulates
the recruitment and activation of cells following tissue injury via
context-dependent transcriptional programs, and thus orchestrates
the full sequence of wound repair, ranging from hemostasis to
remodeling (116-118). FGFR1-mediated signaling serves
a key role in wound repair by orchestrating neovascularization,
extracellular matrix synthesis and structural reorganization of
damaged tissue. This multifaceted regulation ensures coordinated
progression through healing phases, culminating in functional
restoration and preservation of tissue architectural integrity
(119).
Genetic ablation of FGFR1 in murine models results
in increased trabecular bone mass and cortical thickness,
accompanied by impaired osteoclast function and enhanced osteoblast
activity (Table I) (35,120,121). These findings are supported by
pharmacological studies demonstrating that FGFR1 inhibition
attenuates bone erosion and synovitis in experimental arthritis
models (13,122,123). However, the cell type-specific
mechanisms through which FGFR1 coordinates bone destruction in RA
remain incompletely understood, particularly regarding its
interplay with inflammatory mediators and other signaling pathways
such as MAPK, NF-κB and PI3K/AKT pathways (32,123,124).
RA bone destruction is associated with bone tissue
remodeling and maintenance of bone homeostasis. Bone tissue
contains three types of cell: Osteocytes, osteoblasts and
osteoclasts. The most abundant type of cell in adult bones is
osteocytes, which are osteoblasts that differentiate and control
bone remodeling (89,125). Osteocytes regulate osteoblast
differentiation and anabolic action, as well as osteoclastic
activity, either by direct dendritic contact or by the secretion of
regulatory factors such as sclerostine receptor activators and
NF-κB B binders (B ligand-factor nucleic receptor activators,
RANKL) (126). Bone cells are
one of the primary sources of RANKL and FGFR1 serves an important
role in bone development and bone homeostasis. FGFR1 activation
promotes the expression of MMP 2 and RANKL by promoting ERK1/2
phosphorylation (127,128). Mice with FGFR1 and/or FGFR2
deficiency exhibit normal phenotypes at birth, yet develop a high
bone mass phenotype with age (129). These animals show enhanced
periosteal adhesion, expanded and disorganized intracortical bone
and elevated porosity, as well as improved mechanical strength and
stiffness consistent with higher bone mass (129). While KO of specific FGFRs
increases bone mass, mechanical properties such as fracture
toughness are impaired. Despite higher overall bone mass, these
bones show inferior mechanical performance compared with normal
bone. These data establish the role of FGFR1 signaling in
osteoblasts, indicating that FGFR1 is essential for osteoblast
survival and regulation of bone mass during postnatal bone growth
(129). Loss of FGFR1 in
osteocytes activates the Wnt/β-catenin signaling pathway, promotes
trabecular and cortical bone formation and increases
osteoprotegerin mRNA expression and osteoblast activity (35). In addition, the loss of FGFR1 in
osteocytes leads to decreased osteoclast formation, expression of
RANKL mRNA in cortical bone and primary osteocytes and mRNA
expression of genes associated with bone resorption, such as MMP 9
and catechsyn K, suggesting that the signals produced by FGFR1 loss
in osteocytes inhibit osteoclast formation (35). However, these structural
alterations paradoxically coincide with impaired biomechanical
properties, indicating that complete ablation of FGFR1 may disrupt
the equilibrium between bone quantity and quality. While genetic
deletion studies have elucidated the role of FGFR1 in bone
development, the ramifications of pharmacological inhibition in
established RA remain unclear (35,130). Secondly, FGFR1-mediated
regulation of both Wnt/β-catenin and RANKL pathways poses a
challenge in achieving a balanced therapeutic outcome,
necessitating dual pathway modulation strategies. Thirdly, the net
impact of FGFR1 modulation is contingent on its differential
effects on osteocytes, osteoblasts and osteoclasts, underscoring
the importance of cell type-specific responses. Collectively, these
findings position FGFR1 as a promising therapeutic target for
mitigating RA-associated bone loss, and future investigations
should ascertain whether selective, partial inhibition of FGFR1
signaling preserves its physiological functions while curbing
pathological bone destruction in RA.
Osteoclasts are large multinucleated cells whose
primary function is the absorption of bone (142). These cells originate in the
hematopoietic system and differentiate into mature osteoclasts
through the interaction between macrophage colony-stimulating
factors and RANKL. Macrophage colonystimulating factor promotes the
expansion of osteoclast precursors, whereas RANKL induces their
differentiation into functional osteoclasts (132). FGFR1 serves an important role
in osteoclast differentiation and function. Studies have shown that
activated FGFR1 and MAPK act directly on mature osteoclasts to
stimulate bone resorption (143,144). FGFR1 expression is detected on
isolated mouse osteoclasts (145). In addition, FGFR1 expression is
also detected in osteoclasts near fracture sites (146). To explore the direct effect of
FGFR1 on osteoclasts, Lu et al (147) knocked out FGFR1 in mouse bone
marrow mononuclear cells and mature osteoclasts: Mutant mice showed
abnormal bone remodeling, decreased numbers of osteoclasts,
impaired osteoclast function and decreased expression of
tartrate-resistant acid phosphatase and MMP 9. Loss of FGFR1
decreases the number and activity of osteoclasts in mice,
indicating that FGFR1 has a positive regulatory effect on
osteoclasts. FGFR1 is key for the complete differentiation and
activation of mouse osteoclasts (147). FGFR1 directly promotes the
differentiation and activation of osteoclasts by enhancing ERK 1/2
pathway signaling, thus enhancing their ability to decompose bone
(143,147). Aukes et al (148) showed that in the co-culture
environment of osteoclasts and breast cancer cells, FGFR inhibitor
BGJ398 decreases the activation of FGFR-mediated signaling and
expression of osteoclast target genes (149). FGFR1 inhibitors enhance
osteoblast differentiation in vitro and FGFR1 activation
inhibits phosphate metabolism. Overall, FGFR1 maintains bone
balance by modulating osteoblast activities, but the mechanisms and
its full therapeutic potential require further exploration
(150,151).
Angiogenesis serves a key role in maintaining and
promoting the progression of RA (199). Studies have shown that
angiopoietin, hypoxia-inducible factor, VEGF and FGF serve an
important role in inhibiting synovial angiogenesis in RA,
suggesting that targeting angiogenesis may be an effective
treatment for RA (200,201). Binding of these GFs to their
receptors leads to VE cell deformation, division, migration and
proliferation, inducing neovascularization; in addition,
angiogenesis in synovial tissue stimulates intravascular
extravasation, exacerbating synovial inflammation and vessel
formation (202). Targeting
FGFR1 to inhibit angiogenesis has been demonstrated in tumor
therapy (203-205). In RA neovascularization, many
proangiogenic factors, including VEGF and sphingosine-1-phosphate,
induce abnormal activation of VE cells and promote angiogenesis
(206). Studies have shown that
activated FGFR1 upregulates VEGF A expression (207,208). Promoting VEGF A expression and
secretion mediates FGFR1 activation to induce angiogenesis
(209). Lowering FGFR1 protein
levels impairs endothelial cell function, particularly during
angiogenesis (210). FGFR1
activation promotes endothelial cell proliferation and migration by
activating MAPK signaling pathways (211). To the best of our knowledge, no
studies have linked FGFR1 with angiogenesis and bone destruction in
RA. Therefore, investigating the role of FGFR1 in inhibiting
synovial vascularization in RA may facilitate treatment of RA
vascularization and improvement of RA bone destruction. In RA,
FGFR1 is associated with VEGFA production and key endothelial
activities including proliferation and migration. Nevertheless, its
specific roles in synovial angiogenesis and secondary bone damage
remain unclear (Fig. 3).
The contradictory roles of FGFR1 in different cell
types primarily stem from its complex signaling network and cell
type-specific responses (106,212). Environmental factors, cell
type-specific characteristics and stages of disease influence the
ultimate effects of FGFR1. Therefore, when studying FGFR1
functions, it is necessary to consider these factors to understand
its mechanisms of action under different physiological and
pathological conditions (106).
Moreover, targeted therapeutic strategies against FGFR1 need to be
adjusted according to the specific disease and cell type to achieve
the best therapeutic outcome (213). In bone cells, FGFR1 activation
promotes the formation of osteoclasts and bone resorption by
upregulating the expression of MMP 2 and RANKL, leading to a
decrease in bone mass and enhanced bone resorption; FGFR1 also
serves a role in promoting bone formation in bone cells (127,128). The loss of FGFR1 in bone cells
activates the Wnt/β-catenin signaling pathway, promotes the
formation of trabecular and cortical bone and increases the
expression of osteoprotegerin mRNA, thereby enhancing bone
formation (214). The
microenvironment of bone cells, including extracellular matrix
components and local concentrations of GF, may affect FGFR1
signaling pathways, causing it to promote bone resorption or
enhance bone formation. In different stages of RA, bone cell
responses may differ, with early stages dominated by inflammation
and bone resorption, while later stages may involve reparative bone
formation (215). In
osteoblasts, FGFR1 expression is key for bone mineralization and
formation (17). However,
excessive activation of FGFR1 may inhibit osteoblast maturation and
mineralization, leading to decreased bone formation. During
osteoblast development, FGFR1 promotes the proliferation of
progenitor cells and differentiation into pre-osteoblasts in the
early phase. In mature osteoblasts, by contrast, FGFR1 restrains
excessive mineralization to sustain bone homeostasis. Notably,
these biological processes are tightly modulated by multiple
downstream signaling pathways. In articular chondrocytes, FGFR1
activation upregulates the expression of MMP1 and MMP13 in the
matrix, promoting matrix degradation and cartilage damage (216). However, in gene KO models
(128,217), the loss of FGFR1 protects
cartilage from degeneration and decreases cartilage destruction. In
inflammatory diseases such as RA, inflammatory factors may alter
the response of chondrocytes to FGFR1 signaling, causing its role
to shift from protective to destructive (128,154).
As FGFR1 is key for bone resorption and bone
reconstruction in the induction and development of RA, blockade of
FGFR1 might represent a novel therapeutic strategy for the
treatment of RA. There is evidence that mice lacking FGFR1 in
osteocytes have increased trabecular bone mass and cortical bone
thickness, which is attributed to increased bone formation and
impaired bone resorption (35,129). Consequently, FGFR1 is
hypothesized to be a good molecular target for decreasing bone loss
in RA. Tang et al (35)
used osteocyte-specific FGFR1 KO mice to demonstrate that FGFR1
deficiency enhances trabecular bone mass and cortical bone
thickness through augmented bone formation and attenuated bone
resorption. In vitro, Meng et al (14) showed that the FGF pathway is a
critical signaling pathway in relapsed RA, and targeted
tissue-specific inhibition of FGF10/FGFR1 may provide new
opportunities to treat patients with relapse RA. FGFR1 inhibitors
could effectively improve the effectiveness of RA treatment.
Additionally, treating rats with PD173074 (FGFR1 inhibitor)
significantly decreases bone erosion (14).
Drugs used in clinical practice primarily include
non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids and
DMARDs (223,224). Clinical trials have
demonstrated that these drugs effectively improve the condition of
patients with RA (225,226). NSAIDs and glucocorticoids serve
a role in relieving pain and reducing inflammation (227,228). DMARDs are effective first-line
drugs for treating RA in clinical practice (229). FGFR1 inhibitors may inhibit
inflammatory responses, counteract bone erosion, and reduce bone
loss by suppressing the bone-resorbing activity of osteoclasts,
inhibiting chondrocyte degradation, suppressing macrophage
activity, and protecting degenerated chondrocytes. The advantages
of FGFR1 inhibitors in the treatment of RA as well as potential
risks are summarized in Table
III.
FGFR1 is a key regulator in RA-associated bone
destruction, orchestrating crosstalk between synovial angiogenesis,
osteoclast activation and inflammatory signaling. However, the
specific regulatory mechanisms remain unclear, particularly the
signal transduction mechanisms of FGFR1 in the pathogenesis of RA
and across different cell types, which require further validation.
FGFR1 inhibition attenuates bone erosion and synovitis in
preclinical models (230-232), suggesting its therapeutic
potential. However, challenges persist, including the paradoxical
roles of FGFR1 in different cell types and the need for targeted
delivery strategies to minimize off-target effects. Advanced
single-cell sequencing and spatial transcriptomics may delineate
cell-type-specific FGFR1 signaling networks in RA joints. The
therapeutic potential of selective FGFR1 inhibitors, particularly
their capacity to simultaneously target bone erosion and synovitis,
warrants validation in human clinical trials. By bridging these
gaps, FGFR1-targeted therapies may redefine RA management,
particularly for refractory cases with aggressive joint
destruction.
All authors have read and approved the final
manuscript. CQ, ZZ, XW, XL and FLY conceived the study. CQ, HT, JW,
ZY and ZZ constructed figures. CQ and FLY wrote the manuscript.
Data authentication is not applicable.
Not applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
The present study was supported by National Natural Science
Foundation of China (grant nos. 82372412 and 82572767), the Social
Development Project of Jiangsu Province (grant no. BE2022701),
Jiangsu Provincial Traditional Chinese Medicine Science and
Technology Development Program (grant no. MS2023069), Jiangsu
Province Leading Talents Cultivation Project for Traditional
Chinese Medicine (grant no. SLJ0322) and Wuxi Municipal Health
Commission Research Project (grant no. Z202405).
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