FXR in bone metabolism: An emerging regulator

Summary

Farnesoid X receptor (FXR), a core regulator of bile acid metabolism, is also a key modulator of bone metabolism that influences bone remodeling by regulating osteoblast and osteoclast activities. FXR activation promotes the proliferation and differentiation of osteoblasts via pathways such as Wnt/β-catenin, and inhibits osteoclastogenesis through the NF-κB pathway and the RANK/OPG balance. It also regulates chondrocyte function and cartilage integrity, inhibits cartilage-degrading MMP-13, coordinates subchondral bone remodeling to maintain joint health, and acts as a metabolic hub linking the gut, liver, and bone by integrating bile acid and systemic metabolic signals. Dysregulation of this pathway is associated with skeletal complications of non-alcoholic fatty liver disease (NAFLD), obesity and other disorders, and intestinal FXR-mediated FGF15/19 signaling also maintains skeletal homeostasis. FXR activation is a promising therapeutic target for preserving bone density by improving metabolism and alleviating inflammation. This review elucidates its regulatory mechanisms in bone metabolism, laying a foundation for relevant research and translational applications.

Graphical abstract

Cell biology; Functional aspects of cell biology

Introduction

Bone homeostasis is a tightly regulated physiological process that depends on the dynamic equilibrium between osteoblast-mediated bone formation and osteoclast-mediated bone resorption.^1,2,3 Disruption of this balance constitutes the fundamental pathological mechanism underlying prevalent skeletal disorders, such as osteoporosis and osteoarthritis.⁴ Historically, research in bone metabolism has primarily focused on classical hormonal regulators (e.g., estrogen and parathyroid hormone) and local regulatory factors (e.g., the RANKL/RANK/OPG, receptor activator of nuclear factor κB ligand/receptor activator of nuclear factor κB/osteoprotegerin).⁵ However, emerging evidence highlights the significant involvement of metabolic regulatory molecules, particularly the nuclear bile acid receptor farnesoid X receptor (FXR), in the modulation of bone metabolism.^6,7

FXR, encoded by NR1H4 (nuclear receptor subfamily 1 group H member 4), is a ligand-activated nuclear receptor that essential for the regulation of bile acid and lipid homeostasis.⁸ Primary and secondary bile acids (BA) activate FXR-RXR (retinoid X receptor) dependent transcription through downstream mediators such as SHP (small heterodimer partner) and the intestinal FGF15/19 (fibroblast growth factor 15/19) signaling pathway.⁹ Notably, FXR serves as a metabolic mediator linking the intestine, liver, and skeletal system. It integrates bile acid signals with systemic metabolic regulation, transmitting metabolic status information from distant organs (such as the intestine and liver) to bone tissue.^10,11 This “gut-liver-bone axis” provides a mechanistic explanation for the frequent coexistence of skeletal complications such as reduced bone density, increased fracture risk, and accelerated osteoarthritis in metabolic disorders like non-alcoholic fatty liver disease (NAFLD), obesity, and diabetes.^12,13 However, studies on bone metabolism often assess bone resorption and formation separately, which hinders the integration of key regulatory pathways—such as RANKL/OPG, NF-κB (nuclear factor-kappaB), Wnt/β-catenin (Wingless-related integration site/β-catenin), and BMP/Runx2 (bone morphogenetic protein 2/Runt-related transcription factor 2)—obscuring the comprehensive role of FXR in bone remodeling.^{6,14,15,16,17} Given the emerging clinical potential of FXR in maintaining skeletal health, this review aims to elucidate the mechanisms by which FXR regulates bone metabolism and contributes to related pathological conditions. This review will highlight knowledge gaps in current literature and provide direction for future research.

FXR overview and activation mechanisms

FXR is a nuclear receptor that regulates key metabolic processes, including bile acid homeostasis and bone health. This section covers the structure of FXR, its activation by bile acids, and how these mechanisms influence its role in metabolism and bone remodeling.

The structure of FXR

FXR is a member of the nuclear receptor superfamily and exhibits structural features typical of this family.¹⁸ The N-terminal domain (A/B domain) contains a ligand-independent transcriptional activation function domain (AF-1), which varies significantly among different subtypes or isoforms, thereby influencing its basal activity and interactions with coactivators.¹⁹ The deoxyribonucleic Acid (DNA)-binding domain (DBD, C domain) is highly conserved and comprises two zinc finger structures responsible for recognizing and binding to specific DNA sequences known as FXR response elements FXREs in the promoter regions of target genes. The core sequence of farnesoid X receptor response element (FXRE) typically consists of an inverted repeat of the AGGTCA motif separated by one or four nucleotides insulin response element 1 or 4 (IR1 or IR4).¹⁹ The hinge region (D domain) connects the DNA binding domain (DBD) and ligand binding domain (LBD), providing structural flexibility and potentially participating in the binding of localization signals and corepressors.²⁰ The ligand-binding domain (LBD, E/F domain), located at the C-terminus, contains a hydrophobic pocket that recognizes and binds endogenous ligands, primarily bile acids. Ligand binding induces significant conformational changes in the LBD, leading to the dissociation of corepressors (e.g., NCoR, SMRT) and the recruitment of coactivators (e.g., SRC-1, PGC-1α, and CBP/p300).^21,22 These molecular events facilitate the formation of heterodimers between FXR and other nuclear receptors, such as RXRα, which is essential for FXR to bind DNA and exert its biological functions.²³

Classification of FXR

FXR can be classified into two major subtypes: FXRα (NR1H4) and FXRβ (NR1H5, nuclear receptor subfamily 1 group H member 5), which are encoded by distinct genes.²⁴ FXRα serves as the primary and functional subtype and is widely expressed in mammals, playing a central role in regulating bile acid metabolism. In humans and mice, the FXRα gene is located on chromosomes 12q23.1 and chromosome 10, respectively.²⁵ FXRβ is present in most mammalian species; however, in humans and primates, it exists as a non-functional pseudogene that does not encode functional proteins. In rodents, such as mice and rats, the FXRβ gene remains intact, although its physiological function remains largely unclear. It may play a minor role in cholesterol metabolism or adrenal function but is far less significant compared to FXRα. Therefore, in discussions concerning human physiology and pathology, FXR generally refers specifically to FXRα.^26,27

Tissue-specific expression of FXR

FXR expression is predominantly observed in metabolically active tissues and exhibits tissue-specific patterns.²⁸ The liver is the primary organ responsible for bile acid synthesis and recycling, where hepatocytes represent the main site of FXR expression and function. Within the liver, FXR regulates bile acid synthesis, uptake, metabolism, secretion, and transport, thereby maintaining bile acid homeostasis and protecting hepatocytes from bile acid-induced toxicity.^8,29 Hepatic FXR also contributes to metabolic balance and releases endocrine signals—such as FGF15/19—that indirectly promote bone health by reducing systemic inflammation and enhancing osteoblast function.^30,31 Additionally, intestinal epithelial cells, particularly those in the ileum, also express high levels of FXR. The intestine serves as a key site for bile acid reabsorption and microbial metabolism. Upon activation, intestinal FXR modulates bile acid reabsorption, enterohepatic circulation, intestinal barrier integrity, inflammatory responses, and the secretion of gut hormones such as FGF15/19, which subsequently inhibit hepatic bile acid synthesis.¹³ Activation of intestinal FXR further increases FGF15/19 production and attenuates pro-resorptive signaling along the gut-liver-bone axis. The coordinated interaction between hepatic and intestinal FXR integrates multiple physiological inputs and ultimately exerts regulatory influence on bone metabolism.^31,32

Pathophysiological functions of FXR

As a critical metabolic receptor and regulatory hub, dysregulation of FXR function either through insufficient or excessive activation is closely associated with the development of various diseases. FXR activation exerts protective effects in cholestatic liver diseases by suppressing bile acid synthesis (via downregulation of CYP7A1 and CYP8B1) and promoting bile acid excretion into bile ducts (through induction of BSEP[bile salt export pump] and MRP2[multidrug resistance-associated protein 2]).¹³ FXR enhances the efflux of bile acids from hepatocytes into the bloodstream for detoxification via OSTα/OSTβ induction.³³ Impaired FXR function or reduced expression has been implicated in the progression of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).^34,35 FXR agonists, such as obeticholic acid, have already been approved for the treatment of PBC.²⁸ Activation of FXR reduces hepatic cholesterol secretion (by inhibiting ABCG5/G8) while increasing bile acid output (via BSEP induction), thereby lowering bile cholesterol saturation and decreasing the risk of cholesterol gallstone formation.^36,37 In patients with liver cirrhosis, FXR expression and function in the liver are often markedly diminished. FXR activation directly suppresses the activation and proliferation of hepatic stellate cells, reduces extracellular matrix deposition (e.g., collagen), and exerts anti-inflammatory and cholestasis-improving effects, thereby indirectly inhibiting fibrosis progression.²⁹ Additionally, FXR activation may cf. cardiovascular protection by enhancing lipid metabolism (reducing triglycerides and LDL-C while elevating HDL-C), attenuating vascular inflammation, alleviating atherosclerosis, and improving endothelial function.³⁸ Through complex gene regulatory networks, FXR activation exerts multiple protective effects, including promoting bile secretion, protecting the liver, reducing inflammation and fibrosis, and improving metabolic status.^39,40,41 Consequently, FXR dysfunction plays a pivotal role in the pathogenesis of various liver disorders (e.g., cholestasis, NAFLD/NASH, fibrosis), gallstones, intestinal inflammation, and metabolic diseases such as diabetes and obesity.

Bile acids and FXR activation

Bile acids are amphipathic molecules synthesized from cholesterol in the liver. Their primary function involves the emulsification and absorption of dietary lipids. In addition to these classical digestive functions, bile acids serve as potent signaling molecules that regulate metabolic pathways through interactions with nuclear and membrane-bound receptors, particularly FXR and Takeda G-protein receptor 5 (TGR5).⁴² Two major types of bile acids exist: primary and secondary. The principal bile acids in humans cholic acid (CA) and chenodeoxycholic acid (CDCA) are synthesized in hepatocytes via two primary enzymatic pathways: the classical CYP7A1 pathway and the alternative CYP27A1 pathway.⁴³ These bile acids undergo conjugation with taurine or glycine to enhance solubility, after which they are secreted into bile, stored in the gallbladder, and released into the intestine during food intake. Within the gastrointestinal tract, intestinal microbiota modifies primary bile acids into secondary bile acids, such as deoxycholic acid (DCA) and lithocholic acid (LCA), primarily through deconjugation and structural modifications.⁴⁴ This transformation results in a diverse bile acid pool with varying capacities for signaling and receptor binding.⁴⁵ A key aspect of bile acid physiology is the enterohepatic circulation, whereby approximately 95% of bile acids are reabsorbed in the distal ileum and transported back to the liver via the portal vein. This recycling process occurs multiple times daily, and precise regulation ensures cholesterol homeostasis while preventing bile acid-induced toxicity. Bile acids exert systemic effects by activating receptors such as FXR, which detects intracellular bile acid levels and modulates gene expression to inhibit bile acid synthesis, promote its cellular efflux, and facilitate detoxification.⁴⁶ Through interactions with SHP and FGF19/15 signaling pathways, bile acids demonstrate roles beyond digestion, extending to inter-organ communication.⁴⁷

FXR is a nuclear receptor primarily responsible for maintaining bile acid homeostasis in the body. It is predominantly expressed in the liver, intestine, kidneys, and adrenal glands.⁴⁸ Among naturally occurring bile acids, CDCA is recognized as the most potent endogenous activator of FXR. Upon binding of CDCA or other bile acids, FXR forms a heterodimer with RXR, enabling it to bind to FXREs in the promoter regions of target genes.^21,33 One of the primary functions of FXR is the suppression of bile acid synthesis. In mice, FXR induces the expression of FGF15 in the ileum, whereas in humans, it stimulates the production of its ortholog, FGF19.⁴⁹ This hormone is transported to the liver via the portal vein, where it binds to the FGFR4/β-Klotho receptor complex on hepatocytes. This interaction leads to the downregulation of CYP7A1 expression, thereby reducing the activity of cholesterol 7α-hydroxylase, the rate-limiting enzyme in bile acid synthesis. Consequently, FXR and FGF15/19 establish a negative feedback loop that prevents excessive accumulation of bile acids. Additionally, hepatic FXR activation promotes the expression of the SHP, a transcriptional corepressor that lacks DNA-binding capability. SHP interacts with transcription factors such as liver receptor homolog-1(LRH-1) and hepatocyte nuclear factor 4 α(HNF4α), thereby inhibiting the expression of CYP7A1 and CYP8B1, further suppressing bile acid synthesis.⁵⁰ FXR also regulates the expression of bile acid transporters, including the bile salt export pump (BSEP/ABCB11), which mediates the efflux of bile acids from hepatocytes into bile canaliculi.^13,25 FXR governs the expression of multidrug resistance-associated proteins (MRPs), which are involved in bile acid detoxification and excretion.^51,52The following schematic illustrates how bile acids interact with FXR in the liver and ileum to maintain metabolic homeostasis.

According to Figure 1, both liver and ileum cells activate the FXR upon binding of bile acids such as CDCA. FXR activation in the ileum leads to the production of FGF15/19, which is transported to the liver to suppress CYP7A1 expression, thereby regulating bile acid synthesis.⁵³ Additionally, hepatic FXR induces the expression of the SHP protein, which inhibits key transcription factors and facilitates the expression of proteins involved in bile acid metabolism. Through this coordinated regulatory mechanism, bile acid levels are maintained within a physiological range, preventing hepatic injury.⁵⁴

Figure 1.

Bile acid-FXR interaction mechanism

Upon binding to bile acids such as CDCA, FXR induces signaling cascades involving FGF15/19 and small heterodimer partner (SHP) to regulate bile acid synthesis, transport, and detoxification. This mechanistic insight emphasizes the central role of FXR in bile acid regulation and sets the foundation for understanding its systemic effects, including on bone health.

Bile acid signaling and bone homeostasis

Emerging evidence indicates that bile acids play a pivotal role in the regulation of bone homeostasis, primarily through activation of the FXR. While bile acids are traditionally recognized for their roles in lipid digestion and cholesterol metabolism, recent studies have identified their involvement in cross-talk with the skeletal system.^6,11 Bile acids such as CDCA activate FXR, a nuclear receptor expressed in the liver, intestine, and bone cells. FXR activation in osteoblasts promotes their differentiation and mineralization processes essential for bone formation. This effect is partially mediated by the upregulation of transcription factors such as Runx2, which is crucial for osteoblast maturation.⁵⁵ FXR activation inhibits osteoclastogenesis, thereby reducing bone resorption.⁵⁶ The combined suppression of osteoclast activity and stimulation of osteoblast function contribute to enhanced bone formation and preservation.

The gut-liver-bone axis illustrates the interconnected roles of gut bile acid metabolism, hepatic FXR signaling, and skeletal function. Following bile acid synthesis in the liver, bile acids undergo enterohepatic circulation and interact with intestinal FXR, modulating FGF15/19 signaling and influencing metabolic tissues, including bones.^9,14 Disruptions in this axis, such as gut dysbiosis, hepatic dysfunction, or alterations in bile acid composition can impair FXR signaling and lead to adverse skeletal outcomes, including reduced bone mineral density and increased fracture risk.³¹ Moreover, Fxr-deficient animal models exhibit increased bone resorption and decreased trabecular bone mass, further supporting the receptor’s role in maintaining skeletal integrity.^14,55 Clinical evidence also suggests a correlation between metabolic disorders characterized by altered bile acid profiles and compromised bone health, particularly in patients with NAFLD and type 2 diabetes.⁵⁷

CDCA and other bile acids can activate FXR in both the gut and liver, thereby modulating signaling pathways that influence bone remodeling.¹⁴ FXR activation enhances osteoblastogenesis while simultaneously suppressing osteoclastogenesis, thus preserving the dynamic equilibrium between bone formation and resorption.⁷ These findings underscore the significant role of bile acid signaling in the regulation of skeletal physiology.

FXR-mediated regulation of bone remodeling

In addition to its regulatory role in bile acid metabolism, FXR plays a pivotal role in bone remodeling by regulating both bone resorption and formation. This section explores how FXR affects osteoclasts and osteoblasts through various signaling pathways, highlighting its potential as a therapeutic target for bone-related diseases.

FXR inhibits bone resorption

Bone matrix degradation is primarily mediated by osteoclasts, whose activity is tightly regulated.⁵⁸ While osteoclast-mediated resorption is essential for bone remodeling and calcium homeostasis, excessive activity increases the risk of pathological conditions such as osteoporosis. Accumulating evidence supports the notion that FXR actively participates in limiting bone loss by modulating osteoclast differentiation and function.¹⁴ Studies have shown that FXR activation inhibits RANKL-induced NF-κB and MAPK signaling pathways, both of which are critical for osteoclastogenesis.^59,60 By attenuating these signaling cascades, FXR downregulates the expression of key osteoclast-related genes, including TRAP, cathepsin K, and NFATc1, thereby reducing osteoclast formation and preventing excessive bone degradation.^55,61

Animal studies further support the negative regulatory role of FXR in bone resorption. Fxr-deficient mice (Fxr^−/−) exhibit increased osteoclastogenesis and heightened osteoclastic activity, resulting in significant trabecular bone loss and cortical thinning.¹⁴ Serum levels of C-terminal telopeptide of type I collagen (CTX-I), a biochemical marker of bone resorption, are elevated in these models.⁵⁵ In vitro experiments demonstrate that pharmacological activation of FXR reduces osteoclast formation in a dose-dependent manner.⁶

Mechanism of bone resorption inhibition by FXR

FXR exerts anti-resorptive effects through multiple signaling pathways that reduce osteoclastogenesis and dampen inflammatory responses within the bone microenvironment.^14,55 These mechanisms include inhibition of NF-κB signaling, regulation of the RANKL/OPG balance, and suppression of pro-inflammatory cytokine release.^{14,62,63,64,65}

Suppression of NF-κB signaling

The NF-κB pathway plays a central role in osteoclastogenesis. Activation of this pathway is essential for the transcriptional upregulation of osteoclast-specific genes.⁶⁶ The binding of RANKL to its receptor RANK on osteoclast precursors initiates a cascade culminating in the nuclear translocation of NF-κB following IκBα degradation.⁶⁷ FXR has been shown to attenuate RANKL-induced NF-κB activation. It may enhance IκBα expression, thereby preventing NF-κB nuclear translocation by inhibiting IκBα degradation.⁵⁹ FXR can induce the expression of SHP, which interferes with NF-κB coactivator interactions, thereby suppressing its transcriptional activity.⁶⁸ Experimental studies using FXR agonists (e.g., GW4064) have demonstrated a marked reduction in NF-κB activity during osteoclast differentiation.⁶⁹ Consistently, Fxr-deficient models exhibit elevated NF-κB activation, reinforcing the anti-inflammatory, and anti-resorptive functions of FXR.⁷⁰

As a result, NF-κB is prevented from translocating into the nucleus, thereby suppressing the transcription of key inflammatory genes and reducing both inflammation and bone resorption.^64,66,71 The suppression of NF-κB not only aids in mitigating bone erosion but also confers additional anti-inflammatory benefits, reinforcing the therapeutic potential of FXR in diseases associated with pathological bone loss.⁶⁶

Modulation of RANKL/OPG ratio

The RANKL/OPG signaling axis plays a central role in regulating osteoclast differentiation.^72,73 RANKL binds to its receptor RANK on osteoclast precursor cells, promoting their differentiation into mature osteoclasts. Conversely, osteoblasts and stromal cells secrete OPG, a decoy receptor that binds to RANKL and prevents its interaction with RANK, thereby inhibiting osteoclastogenesis.^72,74,75 Activation of FXR enhances this protective pathway, contributing to bone preservation. Numerous in vitro and in vivo studies have demonstrated that FXR agonists reduce RANKL expression while increasing OPG levels, leading to a decreased RANKL/OPG ratio. This shift results in diminished activation of osteoclast precursors and consequently attenuates bone resorption.^14,76 In Fxr-deficient mice, an elevated RANKL/OPG ratio correlates with increased osteoclast activity and greater bone loss, indicating that FXR normally functions to maintain homeostasis within this critical signaling pathway.^6,75 Additionally, FXR-mediated activation of SHP may inhibit transcriptional regulators of RANKL, thereby downregulating its expression.^77,78

Regulation of pro-inflammatory cytokine release

Chronic inflammation significantly contributes to enhanced bone resorption, primarily through the overproduction of pro-inflammatory cytokines, such as TNF-α, interleukin-1 beta (IL-1β), and IL-6.^79,80 These cytokines can directly induce osteoclast differentiation or stimulate stromal and immune cells to produce more RANKL.¹⁵ FXR plays a crucial role in attenuating inflammatory responses by suppressing the expression of these cytokines via direct inhibition of inflammatory gene transcription and enhancement of anti-inflammatory signaling pathways.⁸¹ A key mechanism involves FXR mediated inhibition of NF-κB, a pivotal regulator of cytokine gene expression.⁷⁰ FXR interacts with SHP to prevent the activation of pro-inflammatory genes.⁸² Following FXR activation, TNF-α, IL-1β, and IL-6 are downregulated at both mRNA and protein levels in macrophages and bone marrow-derived cells.^81,83 This effect reduces osteoclastogenic signals within the bone microenvironment. Studies using disease models such as postmenopausal osteoporosis have shown that FXR agonists effectively alleviate inflammation and enhance bone integrity.⁵⁵ Conversely, genetic ablation of Fxr leads to systemic inflammation and elevated levels of pro-inflammatory cytokines, which exacerbate osteoclast activity and promote bone destruction.^55,81,83 Collectively, these findings underscore the pivotal role of FXR in bridging the interaction between the immune system and skeletal homeostasis.

FXR promotes bone formation

FXR has been increasingly recognized for its role in regulating bone metabolism, particularly through the promotion of bone formation processes. While FXR is primarily associated with bile acid homeostasis, its expression in osteoblasts extends its regulatory functions to skeletal development and maintenance. Activation of FXR enhances osteoblast proliferation, differentiation, and survival, thereby facilitating the synthesis and mineralization of the bone matrix.^7,55 FXR promotes bone formation by regulating osteoblast function. FXR stimulates osteoblast proliferation, maturation, and mineralization deposition, which are essential for maintaining skeletal integrity.⁷ Studies on the use of FXR agonists such as obeticholic acid, have reported elevated levels of alkaline phosphatase (ALP) and osteocalcin, indicating enhanced osteoblast activity.⁷ In vitro experiments further demonstrate that FXR activation upregulates RUNX2, a critical transcription factor involved in osteogenic differentiation.⁸⁴ Fxr deficient animal models exhibit reduced bone mass, lower bone density, and diminished osteogenic markers, reinforcing the receptor’s pivotal role in bone remodeling.⁵⁵

Mechanisms by which FXR promotes bone formation

The osteogenic effects of FXR are mediated through multiple interconnected molecular pathways that regulate osteoblast function and bone tissue development. These include key signaling cascades such as Wnt/β-catenin, BMP2/Runx2.^6,15,17 By modulating these pathways, FXR enhances the commitment of mesenchymal stem cells to the osteoblast lineage, promotes extracellular matrix production, and supports the metabolic demands required for sustained bone formation. This section explores the specific signaling and metabolic mechanisms underlying FXR-mediated bone anabolism, highlighting its potential as a multifunctional regulator of skeletal health.

Activation of Wnt/β-catenin signaling

The Wnt/β-catenin signaling pathway plays an important role in regulating osteogenesis. Upon activation, β-catenin accumulates in the cytoplasm and translocates to the nucleus, where it initiates the transcription of genes essential for osteoblast differentiation.⁸⁵ FXR exerts a positive influence on this pathway within osteoblastic cells. Hepatic FXR activation increases the expression of Wnt ligands while suppressing DKK1 (Dickkopf-related protein 1) and sclerostin endogenous inhibitors of β-catenin signaling.⁸⁶ Consequently, enhanced β-catenin signaling in osteoblast progenitors promotes their differentiation into mature, bone-forming cells. Experimental studies confirm that FXR agonists elevate the expression of β-catenin target genes, correlating with improved bone formation. Conversely, Fxr-deficient mice exhibit reduced Wnt/β-catenin activity, impaired osteoblast function, and decreased bone mass.^6,17,55 These findings underscore FXR regulatory role in a critical osteogenic signaling pathway, suggesting its therapeutic potential for treating low bone mass conditions.

Interaction with Runx2 pathways

Runx2 is a key regulator of osteoblast differentiation, which are modulated by FXR to promote bone formation. FXR directly enhances the expression of Runx2, a master transcription factor governing osteoblast lineage commitment and early osteogenic gene expression.⁵⁵ The synergistic activation of Runx2 pathways results in enhanced osteoblast activity and extracellular matrix deposition. Preclinical studies indicate that FXR agonist treatment in bone tissues elevates the expression of osteocalcin and type I collagen, markers of functional osteoblasts.⁸⁷ In contrast, FXR deficiency correlates with reduced Runx2 levels, leading to delayed bone development and impaired mineralization.⁶ Through its modulation of the Runx2 pathway, FXR ensures effective osteoblast function and contributes significantly to bone growth and regeneration.

Regulation of energy metabolism in osteoblasts

Bone growth and structural development are highly energy-demanding processes, necessitating stringent metabolic regulation within osteoblasts.^88,89 This regulation ensures efficient energy utilization by modulating the expression of genes involved in glucose uptake, fatty acid oxidation, and mitochondrial function, thereby supplying osteoblasts with the necessary energy required for bone formation. Upon activation, FXR enhances the expression of PGC-1α and SIRT1, key regulators of mitochondrial biogenesis and function. Consequently, this leads to increased ATP production, reduced cellular susceptibility to harmful substances, and extended survival of bone-forming cells.^{6,49,50,90,91} This collectively creates a favorable energetic environment conducive to bone tissue formation. A deficiency in either energy supply or FXR function results in diminished osteoblast activity, leading to reduced deposition of bone matrix and delayed bone repair. The integrated FXR-SIRT1axis facilitates the elevated ATP requirements of bone formation; its disruption correlates with compromised osteoblast activity and diminished bone mass in metabolic illness contexts.^50,90,91 Therefore, the metabolic actions of FXR effectively link intracellular energy availability with the capacity for bone formation.

Cross-regulation of FXR with PPARγ, LXR, and VDR in bone metabolism

FXR interacts with several nuclear receptors, including peroxisome proliferator-activated receptor gamma (PPARγ), liver X receptor (LXR), and vitamin D receptor (VDR), all of which affect bone metabolism.^92,93 In osteoblasts, PPARγ promotes adipogenic differentiation of mesenchymal stem cells, thereby suppressing osteoblastogenesis, whereas activation of FXR enhances osteoblastic differentiation and inhibits adipogenesis.^6,84,94 In osteoclasts, FXR deficiency has been shown to dysregulate PPARγ/PGC-1β signaling, leading to increased osteoclast formation and enhanced bone resorption, thus linking metabolic disturbances with skeletal remodeling.¹⁴

The LXR pathway, known for its involvement in cholesterol efflux and anti-inflammatory responses, also exerts influence on bone homeostasis. Crosstalk between FXR and LXR affects sterol composition in osteoblast membranes and modulates inflammatory status, consequently impacting osteogenic potential.^79,95,96 This interaction underscores the connection between lipid metabolism and bone integrity.

FXR and VDR share common transcriptional co-activators, and converge on signaling pathways that regulate the RANKL/OPG balance and NF-κB activity.^97,98 Vitamin D-mediated signaling may modulate FXR’s effects on osteoblast mineralization and osteoclast differentiation.⁹⁸ These findings suggest that coordinated targeting of FXR in conjunction with PPARγ, LXR, and VDR pathways may offer synergistic benefits for improving skeletal health.

FXR and bone metabolic diseases

An overview of FXR regulatory functions in skeletal disorders is depicted below to highlight its therapeutic relevance in bone metabolism.

According to the Figure 2, FXR regulates bone homeostasis through dual actions on osteocytes and via the gut-joint axis, alleviating osteoporosis and osteoarthritis.RANKL/RANK signaling drives osteoclast differentiation and bone resorption by activating TRAF6, MAPK, NF-κB, and PI3K/Akt cascades, contributing to osteoporosis development. FXR agonists promote osteoblast differentiation by upregulating osteogenesis-related genes such as RUNX2. In osteoarthritis, intestinal FXR (activated by UDCA/GUDCA) enhances GLP-1 secretion, which inhibits intra-articular p-JNK and downstream catabolic factors (MMP-9, CTSK), thereby protecting subchondral bone and alleviating osteoarthritis.

Figure 2.

Multifaceted roles of the FXR in bone metabolism and diseases

FXR influences osteoblasts (OBs) and osteoclasts (OCs), modulates inflammatory responses, and maintains cartilage and subchondral bone integrity, making it a key therapeutic target in osteoporosis (OP) and OA.

Osteoporosis (OP)

Osteoporosis (OP) is a prevalent systemic skeletal disorder predominantly affecting middle-aged and elderly individuals. It is characterized by deterioration of bone microarchitecture and reduced bone mass, which collectively increase the susceptibility to fractures. As a global health concern, OP affects more than 200 million individuals worldwide, according to epidemiological statistics.⁹⁹

Emerging evidence suggests that FXR is implicated in the pathogenesis and therapeutic management of osteoporosis.¹⁴ Its mechanism of action is multifaceted, involving the bidirectional regulation of bone formation and resorption, as well as its interaction with the gut microbiota commonly referred to as the “gut-bone axis”.^31,100,101

Bone tissue contains bile acids, which are derived from the serum and can be released in significant amounts into the bone microenvironment during the process of bone resorption.¹⁰² Previous studies have demonstrated that activation of FXR enhances the expression of osteoblast-specific marker genes, including bone sialoprotein (BSP), osteocalcin, osteopontin, and ALP.⁸⁴ Furthermore, the FXR antagonist suppresses the transcription of key osteogenic genes, such as osteocalcin, osteopontin, reduces ALP activity, and consequently impairs osteogenic capacity.^6,84,103

In vivo and in vitro studies conducted by Dong et al. revealed that mice with Fxr deficiency in bone marrow mesenchymal stem cells (BMSCs) and osteoblasts exhibited delayed skeletal development and osteoporotic phenotypes.⁵⁵ Mechanistically, FXR may enhance osteogenic activity by stabilizing Runx2 through the inhibition of Thoc6-mediated ubiquitination. Additionally, activated FXR can directly bind to the promoter region of Thoc6 and suppress its expression. The interaction between Runx2 and Thoc6 is mediated by the Runt domain of Runx2 and the WD repeat domain of Thoc6.

FXR deficiency has been shown to promote osteoclastogenesis. Specifically, the absence of FXR accelerates osteoclast formation by downregulating c-Jun N-terminal kinase (JNK) 1/2 expression.^14,104 The upregulation of PPARγ and its coactivator PGC-1β appears to mediate this osteoclastic effect via the JNK signaling pathway. Further investigations have revealed that FXR deficiency leads to decreased expression of IFN-β through the RANKL signaling pathway, which is a potent inhibitor of osteoclastogenesis.¹⁴ The study also proposes that FXR deficiency disrupts IFN-β-regulated downstream signaling via the JAK3-STAT1 pathway, thereby enhancing osteoclast formation.¹⁴ These findings indicate that FXR functions as a negative regulator of osteoclast differentiation and represents a promising therapeutic target for postmenopausal osteoporosis and disuse-induced bone loss. Collectively, our results endorse a scenario whereby FXR deficiency enhances the PPARγ/PGC-1β axis and diminishes JNK1/2, aligning with nuclear-receptor interactions that alter the osteoblast-osteoclast equilibrium in favor of resorption.

In accordance with a gut-liver-bone framework, intestinal FXR–FGF15/19 signaling, together with hepatic FXR regulation of bile-acid/metabolic tone, collaboratively influences osteoblast-osteoclast coupling, especially in conditions of dysbiosis or metabolic stress.³¹ Accordingly, under metabolic stress (e.g., obesity/insulin resistance), attenuation of the FXR-SIRT1 axis may constrain osteoblast bioenergetics and shift remodeling toward resorption.^105,106 SH-479 is a pentacyclic triterpenoid compound capable of dual activation of TGR5 and FXR. Compared to selective agonists targeting either FXR or TGR5 alone, SH-479 demonstrates superior efficacy in suppressing osteoclastogenesis while simultaneously promoting osteoblast formation.⁵⁶ Specnuezhenide (SPN), a cyclic ether terpenoid glycoside isolated from ligustrum lucidum, has been shown to improve bone microarchitecture and increase bone mass in mice following oral administration, primarily through the stimulation of osteogenesis and inhibition of osteoclast activity.⁷⁶

The Table 1 below summarizes the major FXR agonists and inhibitors that have been investigated for their roles in bone metabolic diseases. It provides an overview of their cellular targets, effects, and associated signaling pathways. This compilation highlights the potential of FXR modulation in treating skeletal disorders by influencing bone formation and resorption processes.

Table 1.

FXR agonists/inhibitors in osteoporosis or osteoarthritis

Agonists/Inhibitors	Target molecule(s)	Effects	In vitro/in vivo	Signaling pathways	Bone formation↑/bone resorption↓	Reference
Obeticholic acid	FXR↑	Enhances osteoblast activity and bone formation	In vivo (mice); In vitro (osteoblast)	FXR-SHP-Runx2, Wnt/β-catenin activation	Bone formation↑	Xiang et al.101
GW4064	FXR↑	Reduces osteoclastogenesis and inflammation	In vitro (osteoclast)	FXR-NFATc1-RANKL inhibition, NF-κB suppression	Bone resorption↓	Hu et al.69
Guggulsterone	FXR↓	Suppresses osteogenic gene expression and ALP activity	In vitro (osteoblast)	Inhibits FXR-Runx2/ALP, BMP2 suppression	Bone formation↓	Lu et al.107
SH-479	FXR↑, TGR5↑	Dual activation reduces osteoclastogenesis and promotes osteoblast differentiation	In vivo (OVX mice); In vitro (osteoblast/osteoclast)	FXR-SHP, TGR5-cAMP/PKA, NF-κB, RANKL-OPG modulation	Bone Formation ↑, Bone Resorption ↓	Guan et al.108
Specnuezhenide (SPN)	FXR↑	Improves bone microarchitecture and increases bone mass	In vivo (mice, oral administration)	FXR-FGF15/19-MAPK, Runx2 activation	Bone formation ↑	Deng et al.76

Due to their ability to modulate bile acid homeostasis, lipid metabolism, and inflammatory responses, FXR agonists—such as obeticholic acid (OCA) and tropifexor—are currently under clinical investigation for the treatment of non-alcoholic steatohepatitis (NASH).¹⁰⁹ OCA was the first FXR agonist demonstrated to be effective in clinical trials, and preliminary results from its phase 3 trial consistently show favorable outcomes in improving liver fibrosis.¹¹⁰ However, its clinical use is limited by adverse effects, including pruritus and dyslipidemia, which have prevented regulatory approval for NASH treatment to date. Preclinical studies have also indicated that OCA may ameliorate bone loss in ovariectomized mouse models of osteoporosis.⁵⁵ Nevertheless, the potential application of FXR agonists like OCA and tropifexor in bone-related disorders requires further investigation to fully assess their efficacy and safety. Therefore, enhancing tissue selectivity, improving safety profiles, and implementing stratified treatment strategies for patients with comorbid conditions may be essential for realizing the therapeutic potential of FXR agonists in bone diseases.

Osteoarthritis (OA)

OA is a prevalent degenerative joint disease that significantly contributes to joint pain, functional disability, and a diminished quality of life, thereby posing a serious threat to global public health. Recent studies indicate that the prevalence of OA among individuals aged 65 years and older exceeds 50%.¹¹¹ In Western countries, the economic burden associated with OA accounts for approximately 2.5% of the gross domestic product (GDP), making it one of the leading contributors to healthcare expenditure.¹¹² With the continuous rise in life expectancy and the accelerating aging of the population in our country, OA being the most common age-related musculoskeletal disorder is expected to attract increasing clinical and societal attention in the coming years.

FXR is primarily recognized for its roles in metabolic regulation and liver function, recent studies have highlighted its significant involvement in joint tissues such as cartilage, chondrocytes, and subchondral bone. Within these tissues, FXR plays a crucial role in regulating cell survival, extracellular matrix (ECM) development, and bone formation.⁸⁴ This section explores how FXR modulates chondrocyte function, maintains cartilage integrity, and influences subchondral bone dynamics collectively positioning FXR as a potential therapeutic target for osteoarthritis.

Studies have demonstrated the presence of FXR in articular cartilage. While traditionally studied in hepatic and intestinal tissues, emerging evidence suggests that FXR expression can be upregulated under inflammatory or stress conditions within cartilage.⁶⁹ Activation of FXR contributes to the regulation of chondrocyte differentiation and survival. These mechanisms contribute to the structural integrity and resilience of cartilage, potentially delaying the progression of osteoarthritis. Collectively, these findings suggest that FXR is not only present in cartilage tissue but also plays a protective role in chondrocytes, making it a promising candidate for early intervention in osteoarthritis.

Cartilage homeostasis relies on a dynamic equilibrium between the synthesis and degradation of the ECM.^113,114 FXR has emerged as a key regulator in this process by modulating the expression of genes involved in ECM protein production and catabolic enzyme activity. FXR activation leads to increased levels of type II collagen and aggrecan, two principal components of the cartilage ECM.⁶⁹ Additionally, FXR inhibits the expression of MMPs, particularly MMP-13, which are elevated in osteoarthritic cartilage and responsible for collagen degradation.^69,115 In experimental models of osteoarthritis, FXR agonists have been shown to alleviate cartilage damage and reduce inflammation.⁶⁹ Taken together, these findings indicate that FXR preserves cartilage structure by promoting ECM synthesis, inhibiting catabolism, and suppressing inflammatory pathways.

Subchondral bone, the layer of bone underlying articular cartilage, plays an integral role in the pathogenesis of OA. FXR is expressed in both osteoblasts and osteoclasts and regulates their activities, thereby influencing bone remodeling and biomechanical adaptation.⁶ Activation of FXR promotes osteoblastogenesis while inhibiting osteoclast differentiation, favoring bone formation over resorption.⁵⁵ This regulatory mechanism may be particularly relevant in subchondral bone. Disruption of FXR signaling in subchondral bone has been linked to accelerated OA progression, underscoring its importance in maintaining joint integrity.⁶⁹ By influencing both cartilage and bone metabolism, FXR contributes to osteochondral homeostasis and represents a promising therapeutic avenue for degenerative joint diseases.

Research limitations and future perspectives

The current research is subject to several limitations. Given that FXR is widely expressed across multiple organs—including the liver, intestine, immune system, and adipose tissue—its activation may disrupt bile acid and lipid homeostasis, potentially leading to gallbladder and gastrointestinal complications. FXR agonists have been associated with increased LDL-C levels, while TGR5 activation may induce gallbladder distension and pruritus.^116,117 Systemic dual agonists could pose a risk of metabolic disturbances (e.g., glucose and lipid dysregulation) in susceptible populations, such as those with type 2 diabetes or obesity. Therefore, future efforts should focus on developing highly selective FXR agonists—such as nanoparticle-based or bone-targeting peptide systems—for site-specific delivery to bone tissue, while closely monitoring their systemic effects on bile acid and lipid metabolism. The potential synergistic effects of selective FXR modulators (SEFMs) in combination with anti-resorptive agents (e.g., bisphosphonates or denosumab) may help minimize off-target actions.^118,119,120

Considering the growing therapeutic promise of FXR activation, subsequent research must prioritize addressing key knowledge gaps. This includes the use of conditional FXR knockout animal models with targeted deletions in bone and intestinal cells to better define the tissue-specific roles of FXR in skeletal health. Furthermore, elucidating the interaction between FXR and gut microbiota-derived metabolites is critical, as this axis may offer novel insights into the regulation of bone metabolism via the gut-liver-bone pathway. Additionally, combining FXR agonists with established anti-osteoporotic therapies—such as denosumab or parathyroid hormone analogues—may enhance treatment efficacy for osteoporosis and related skeletal disorders through coordinated modulation of bone formation and resorption.

Conclusions

FXR, traditionally recognized for its pivotal role in bile acid metabolism, has recently emerged as a key regulator of bone homeostasis.^55,121 Accumulating evidence indicates that FXR plays a multifaceted role in maintaining skeletal integrity, including bone architecture, cartilage preservation, and subchondral bone equilibrium. Through the modulation of both osteoblastic and osteoclastic activity, FXR promotes bone formation and suppresses resorption, thereby contributing to skeletal balance.¹⁴ FXR influences several critical signaling pathways—such asNF-κB, Wnt/β-catenin, Runx2, and RANKL/OPG—and regulates energy metabolism within bone cells.^7,55 Furthermore, FXR is involved in cellular differentiation, joint tissue maintenance, and the modulation of inflammatory responses, thus impacting both the onset and progression of osteoarthritis.^14,122 As a molecular link between metabolic and skeletal systems, FXR illustrates how metabolic disorders—including NAFLD, can adversely affect bone health.^123,124

Given its roles in regulating inflammation, lipid and glucose homeostasis, and bile acid metabolism, FXR represents a promising therapeutic target for metabolic-related musculoskeletal diseases. Further exploration of tissue-specific FXR mechanisms and the development of selective FXR agonists may yield novel interventions for osteoporosis, osteoarthritis, and other metabolic bone disorders. A deeper understanding of the gut-liver-bone axis will facilitate the clinical translation of FXR-targeted therapies in skeletal conditions. By integrating metabolic regulation with skeletal biology, FXR-based therapeutic strategies offer significant potential for the management of diverse skeletal pathologies.

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (Nos. 82102626).

Author contributions

S.M.M.H.R. and A.S. contributed to the compilation of relevant references and the drafting of this article. Y.K. was responsible for the preparation of figures and tables. S.T. and H.L. contributed to the conceptualization of the article and revised its academic content. All authors reviewed and approved the final version of this paper.

Declaration of interests

The authors declare no competing interests.