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Research progress on the effects of macrophage‑derived exosomes on muscle factors IGF‑1 and FGF‑2 mediating musculoskeletal crosstalk molecular signaling pathway on bone metabolism (Review)

  • Authors:
    • Ruo-Mei Cui
    • Mai Zheng
    • Jian-Bin Hong
    • Zheng-Xiang Wang
    • Yu-Fang Cun
    • Shu-Ji Gao
    • Yan-Lin Zhu
    • Zi-Bin Yang
    • Ming-Wei Liu
  • View Affiliations / Copyright

    Affiliations: Department of Rheumatology, The First Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650032, P.R. China, Department of Orthopedics, Dali Bai Autonomous Prefecture People's Hospital, Dali, Yunnan 671000, P.R. China, Department of Spinal Surgery, Dali Bai Autonomous Prefecture People's Hospital, Dali, Yunnan 671000, P.R. China, Department of Pharmacy, Dali Bai Autonomous Prefecture People's Hospital, Dali, Yunnan 671000, P.R. China, Emergency Department, The First Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650032, P.R. China, Emergency Department, Dali Bai Autonomous Prefecture People's Hospital, Dali, Yunnan 671000, P.R. China
    Copyright: © Cui et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 67
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    Published online on: January 21, 2026
       https://doi.org/10.3892/ijmm.2026.5738
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Abstract

Musculoskeletal crosstalk is essential for maintaining the balance of bone metabolism, with macrophage‑derived exosomes emerging as key regulators of this process. Exosomes, small extracellular vesicles secreted by cells, carry a variety of bioactive molecules; proteins, lipids, mRNAs and miRNAs and facilitate intercellular communication by transferring these cargos to recipient cells. Specifically, macrophage‑derived exosomes mediate muscle‑bone interactions by transferring key regulators such as insulin‑like growth factor‑1 (IGF‑1) and fibroblast growth factor‑2 (FGF‑2), thereby playing a pivotal role in bone metabolic homeostasis. Macrophages are classified into pro‑inflammatory M1 and anti‑inflammatory M2 phenotypes, each performing distinct functions in immune responses. Exosomes from M1 macrophages typically carry pro‑inflammatory factors that can activate osteoclastic bone resorption, disrupting bone metabolism in pathological conditions. By contrast, exosomes from M2 macrophages often contain anti‑inflammatory factors that promote tissue repair and bone formation. In the context of bone metabolism, exosomes from M1 and M2 macrophages modulate muscle‑bone signaling by delivering regulators that influence the expression of IGF‑1 and FGF‑2, affecting osteoblast proliferation, differentiation, and mineralization. M1 macrophage‑derived exosomes activate signaling pathways such as NF‑κB and MAPK through the transfer of pro‑inflammatory cargo, thereby enhancing bone resorption. By contrast, exosomes from M2 macrophages can suppress pro‑inflammatory signaling while activating pathways like TGF‑β and PI3K/Akt, promoting bone synthesis and repair. As critical myokines, IGF‑1 and FGF‑2 not only support muscle growth, repair, and maintenance but also directly influence bone remodeling through musculoskeletal crosstalk.

View Figures

Figure 1

Regulatory mechanism of mechanical
signal transduction on the musculoskeletal system. Mechanical
stress inhibits the Hippo pathway, activating Wnt/β-catenin
signaling. It also suppresses sclerostin, further promoting Wnt
pathway activation. Additionally, mechanical stress regulates
integrins to activate the FAK and RhoA/ROCK pathways, stimulating
osteoblasts and other bone-related cells, thus promoting bone
mineralization. Furthermore, mechanical stress regulates muscle
growth through activation of AMPK, PI3K/Akt/mTORC1, and
mitochondrial metabolism-related pathways. FAK, Focal adhesion
kinase; RhoA, Ras homolog gene family member A; ROCK,
Rho-associated kinase; AMPK, Adenosine monophosphate-activated
protein kinase; PI3K, phosphatidylinositol-3-kinase; Akt, protein
kinase B; mTORC1, mammalian target of rapamycin complex 1; PGC-1α,
Peroxisome proliferators-activated receptor γ coactivator 1α.

Figure 2

Regulatory pathways of muscle factors
on the musculoskeletal system. IGF-1 modulates muscle metabolism
via the PI3K/Akt/mTOR pathway and bone metabolism through PI3K/Akt
and MAPK/ERK signaling. FGF-2 regulates muscle metabolism via
MAPK/ERK and bone metabolism through BMP-2/Smad signaling.
Myostatin influences muscle metabolism via Smad3 and P21, and bone
metabolism through Smad2 and Wnt/β-catenin pathways. PGC-1α
stimulates PNDC5, promoting Irisin release from muscle; Irisin
subsequently regulates bone metabolism via P38MAPK/ERK and
RANKL/NFATc1 signaling. IGF-1, Insulin-like growth factor-1; FGF-2,
Fibroblast growth factor 2; GSK3, Glycogen Synthase Kinase-3;
IGFBP-3, insulin-like growth factor binding protein 3; IGFBP-5,
insulin-like growth factor binding protein 5; MyoD, Myoblast
determination protein 1; PNDC, peroxynitrite decomposition
catalyst; Irisin, human recombinant; Runx2, Runt-related
transcription factor 2; PI3K, phosphatidylinositol-3-kinase; Akt,
protein kinase B; mTOR, mammalian target of rapamycin; PGC-1α,
peroxisome proliferators-activated receptor γ coactivator 1α;
RANKL, receptor activator of nuclear factor-κB ligand; NFATc1,
nuclear factor of activated T cells; MAPK, mitogen-activated
protein kinase; ERK, extracellular signal-regulated kinase; BMP-2,
bone morphogenetic protein type 2; Smad3, mothers against
decapentaplegic homolog 3; Wnt, wingless-related integration
site.

Figure 3

Regulatory mechanism of estrogen on
the musculoskeletal system. Estrogen modulates bone metabolism
through PI3K/Akt, MAPK/ERK, RANKL/OPG, and Wnt/β-catenin pathways.
In muscle, estrogen influences metabolism via PI3K/Akt/mTOR,
GPER/MAPK/ERK, RANKL/OPG, and MuRF1/MAFbx pathways. GPER, G
protein-coupled estrogen receptor; ERβ, estrogen receptor beta;
ERα, estrogen receptor alpha; Runx2, Runt-related transcription
factor 2; PI3K, phosphatidylinositol-3-kinase; Akt, protein kinase
B; mTOR, mammalian target of rapamycin; MAPK, mitogen-activated
protein kinase; ERK, extracellular signal-regulated kinase; RANKL,
receptor activator of nuclear factor-κB ligand; OPG,
osteoprotegerin; MAFbx, muscle atrophy F-box; MuRF1, muscle RING
finger-1.

Figure 4

Regulatory mechanism of IGF-1 on the
musculoskeletal system. IGF-1 modulates bone metabolism through
several signaling pathways, including Wnt/β-catenin, PI3K/Akt,
MAPK, RANKL/OPG, and Akt. It also influences muscle metabolism via
the PI3K/Akt/mTOR, MuRF1/MAFbx, and GLUT4 pathways. Wnt,
ςingless-type MMTV integration site family; Bcl-2, B-cell
lymphoma-2; GH, growth hormone; IGF-1, insulin-like growth factor
1; PI3K, phosphatidylinositol-3-kinase; Akt, protein kinase B;
mTOR, mammalian target of rapamycin; MAPK, mitogen-activated
protein kinase; ERK, extracellular signal-regulated kinase; RANKL,
receptor activator of nuclear factor-κB ligand; OPG,
osteoprotegerin; MAFbx, muscle atrophy F-box; MuRF1, muscle RING
finger-1; GLUT4, Glucose transporter protein 4.

Figure 5

Regulatory mechanism of FGF-2 on the
musculoskeletal system. FGF-2 regulates bone metabolism through the
ERK, JAK-STAT, PI3K/Akt, and RANKL/OPG pathways. In muscle, it
affects metabolism via AMPK/PGC-1α, AMPK/SIRT-1, PGC-1α/GLUT4,
PGC-1α/IRS-1, FOXO-3/Atrogin-1 and FOXO-3/MuRF-1 signaling. FGF-2,
Basic fibroblast growth factor; JAK, Janus kinase; STAT, Signal
transducers and activators of transcription; PI3K,
phosphatidylinositol-3-kinase; Akt, protein kinase B; mTOR,
mammalian target of rapamycin; Atrogin-1, muscle atrophy-1; PR,
progesterone receptors; FGFR, fibroblast growth factor receptor;
AMPK, AMP-activated protein kinase; PGC-1α, peroxisome
proliferator-activated receptor gamma coactivator 1 alpha; MAPK,
Mitogen-activated protein kinase; ERK, Extracellular
signal-regulated kinase; RANKL, receptor activator of nuclear
factor-κB ligand; OPG, Osteoprotegerin; MuRF1, muscle RING
finger-1; GLUT4, Glucose transporter protein 4; SIRT1, Sirtuin1;
IRS1, Insulin receptor substrate 1; FOXO-3, Forkhead box O3.

Figure 6

Regulation of bone remodeling
signaling pathways by M1 exosomes. M1 macrophage-derived exosomes
contain specific microRNAs, including miR-1246, miR-98, miR-122 and
miR-155, that regulate bone metabolism by targeting key signaling
molecules. Specifically, miR-1246 downregulates GSK3B and Axin2;
miR-98 suppresses DUSP-1; miR-122 inhibits Bcl-2 and miR-155
represses both BMP and SOCS6. Additionally, these exosomes modulate
bone remodeling through the NF-κB signaling pathway. miRNAs/miRs,
microRNAs; M1 Exo, M1 macrophage-derived exosomes; Omap, Office of
Medical Assistance Programs; GSK3B, Glycogen synthase kinase 3
beta; DUSP-1, Dual specificity phosphatase 1; Bcl-2, B-cell
lymphoma/Leukemia-2; BMP, Bone morphogenetic protein; Axin2, Axis
inhibition protein 2; JNK, c-Jun N-terminal kinase; SOCS6,
suppressor of cytokine signaling 6; BMMSC, Bone marrow mesenchymal
stem cells; NF-κB, Nuclear factor kappa B.

Figure 7

Regulation of bone remodeling
signaling pathways by M2-derived exosomes. Exosomes derived from M2
macrophages carry miRNAs such as miR-378a, miR-99a, miR-146b,
miR-378a, and miR-690, which positively influence bone metabolism.
These miRNAs act through multiple targets, miR-378a enhances BMP
signaling; the miR-99a/146b/378a cluster inhibits NF-κB; and
miR-690 suppresses both NF-κB p65 and IRS-1 while promoting TAZ
activity. Furthermore, M2 exosomes contribute to bone regulation by
modulating the behavior of BMMSCs. miRNAs/miRs, microRNAs; BMP,
Bone morphogenetic protein(s); NF-κB, Nuclear factor kappa B; IRS1,
Insulin receptor substrate 1; OCN, osteocalcin; TAZ,
Transcriptional co-activator with PDZ-binding motif; BMMSCs, Bone
marrow mesenchymal stem cells.

Figure 8

Mechanism of macrophage-derived
exosomes on bone metabolism and musculoskeletal crosstalk. M2
macrophage-derived exosomes regulate muscle metabolism through
several pathways, the miR-23a/MuRF1/MAFbx axis, C/EBP-β/PPARγ
signaling, miR-206/HDAC4, Akt/mTOR signaling, and by modulating M1
macrophage activity. Concurrently, macrophage-derived exosomes
regulate bone metabolism via the PI3K/Akt and Wnt/β-catenin
pathways, miR-1481/PTEN and miR-21/PTEN axes, and the UCHL3/SMAD1
signaling cascade. miRNAs/miRs, microRNAs; PPARγ, Peroxisome
proliferator-activated receptor gamma; mTOR, mammalian target of
rapamycin; PI3K, phosphatidylinositol-3-kinase; Akt, protein kinase
B; MuRF1, muscle RING finger-1; MAFbx, F-box only protein 32;
Smad1, SMAD family member 1; Wnt, wingless-type; MMTV integration
site family; TGF-β, transforming growth factor beta; HDAC4, histone
deacetylation 4; C/EBP-β, CCAAT-enhancer binding protein; UCHL3,
ubiquitin carboxyl terminal hydrolase L3; ALP, alanine phosphatase;
MyoD, myogenic differentiation 1; MYOG, Human myogenin; BMMSC, Bone
marrow stromal cells; PTEN, Phosphatase and tensin homolog; RUNX2,
Runt-related transcription factor 2.

Figure 9

Mechanism of macrophage-derived
exosomes on bone metabolism and musculoskeletal crosstalk by
regulating IGF-1 expression. M2 macrophage-derived exosomes are
enriched with miR-29a, circ-Eif3c, and IGF-1. miR-29a and
circ-Eif3c regulate bone and muscle metabolism by modulating the
IGF-1/PI3K/Akt signaling pathway. Independently, IGF-1 regulates
muscle metabolism by inhibiting the MuRF1/MAFbx and NF-κB pathways.
IGF-1, insulin-like growth factor 1; miRNAs/miRs, microRNAs; circ,
circular RNA; PI3K, phosphatidylinositol-3-kinase; Akt, protein
kinase B; MuRF1, muscle RING finger-1; MAFbx, F-box only protein
32; NF-κB, Nuclear factor kappa B.

Figure 10

Mechanism of macrophage-derived
exosomes on bone metabolism and musculoskeletal crosstalk by
regulating FGF-2 expression. Macrophage exosomes contain miR-21-5p,
miR-29a, lncRNA H19, and FGF-2. The miRNAs and lncRNA H19 regulate
muscle metabolism by targeting FGF-2, activating PI3K/Akt
signaling, and promoting the expression of myogenic factors MyoD
and Myogenin. FGF-2 regulates both muscle and bone metabolism
through the TGF-β/SMAD3, PI3K/Akt/mTOR, and FOXO-3 pathways.
miRNAs/miRs, microRNAs; lnc, long non-coding; FGF-2, basic
fibroblast growth factor; PI3K, phosphatidylinositol-3-kinase; Akt,
protein kinase B; MuRF1, muscle RING finger-1; MyoD, Myogenic
differentiation 1; ERK, extracellular regulated protein kinases;
RUNX2, Runt-related transcription factor 2; TGF-β, transforming
growth factor beta; SMAD3, Mothers against decapentaplegic homolog
3; mTOR, mammalian target of rapamycin; FOXO, forkhead box O;
Atrogin-1, muscle atrophy-1.

Figure 11

Regulatory mechanism of estrogen
deficiency on bone metabolism during osteoporosis. Estrogen
deficiency leads to reduced muscle synthesis and increased protein
breakdown, resulting in muscle atrophy. Specifically, it decreases
IGF-1 synthesis, inhibiting the PI3K/Akt/mTOR pathway and reducing
muscle fiber protein synthesis. Concurrently, elevated MuRF1/MAFbx
activity promotes muscle degradation. Impaired PGC-1α function
reduces mitochondrial biogenesis, electron transport chain activity
and ATP production. Increased PINK1/Parkin-mediated mitophagy
clears dysfunctional mitochondria. Enhanced M1 macrophage activity
contributes to muscle tissue inflammation. PI3K,
phosphatidylinositol-3-kinase; Akt, protein kinase B; MuRF1, muscle
RING finger-1; IGF-1, insulin-like growth factor 1; mTOR, mammalian
target of rapamycin; PGC-1α, Peroxisome proliferator-activated
receptor γ coactivator 1α; MAFbx, F-box only protein 32; PINK1,
PTEN-induced putative kinase 1; ATP, Adenosine triphosphate; Bax,
Bcl-2-associated X protein; BAK, BCL-2 antagonist killer 1.

Figure 12

Regulatory mechanism of estrogen
deficiency on muscle metabolism during osteoporosis. Estrogen
deficiency disrupts bone remodeling by decreasing PGC-1α and
elevating SOST and FSH, leading to increased inflammatory cytokines
(such as IL-1, IL-6, IL-17 and TNF-α) and oxidative stress. These
changes promote osteoclast differentiation and enhance bone
resorption. Simultaneously, MSCs shift differentiation potential
toward adipogenesis at the expense of osteogenesis. This imbalance
between increased bone resorption and decreased bone formation
results in impaired bone remodeling and net bone loss. PGC-1α,
Peroxisome proliferator-activated receptor γ coactivator 1α; SOST,
Sclerostin; FSH, Follicle-stimulating hormone; MSCs, Mesenchymal
stem cells.

Figure 13

Regulatory mechanism of sarcopenia on
bone metabolism during osteoporosis. Sarcopenia, characterized by
the loss of muscle mass and reduced mechanical loading, leads to
decreased osteogenic activity and bone formation. Impaired muscle
contraction reduces Wnt/β-catenin signaling, inhibiting osteoblast
differentiation. Declines in IGF-1 synthesis suppress PI3K/Akt/mTOR
activity, further impairing osteoblast differentiation. Increased
inflammatory cytokines elevate RANKL expression and suppress OPG,
enhancing osteoclast activity and bone resorption. Reduced vitamin
D intake decreases intestinal calcium absorption and bone
formation. Muscle atrophy triggers a stress response, increasing
norepinephrine production and sustained β2-AR activation, which
promotes adipogenic differentiation of bone marrow mesenchymal stem
cells. Muscle mitochondrial dysfunction reduces ATP synthesis,
inhibits SERCA activity, causes intracellular calcium overload, and
induces osteoblast apoptosis. PI3K, phosphatidylinositol-3-kinase;
Akt, protein kinase B; IGF-1, insulin-like growth factor 1; mTOR,
mammalian target of rapamycin; ATP, Adenosine triphosphate; RANKL,
receptor activator of nuclear factor-κB ligand; OPG,
osteoprotegerin.
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Copy and paste a formatted citation
Spandidos Publications style
Cui R, Zheng M, Hong J, Wang Z, Cun Y, Gao S, Zhu Y, Yang Z and Liu M: <p>Research progress on the effects of macrophage‑derived exosomes on muscle factors IGF‑1 and FGF‑2 mediating musculoskeletal crosstalk molecular signaling pathway on bone metabolism (Review)</p>. Int J Mol Med 57: 67, 2026.
APA
Cui, R., Zheng, M., Hong, J., Wang, Z., Cun, Y., Gao, S. ... Liu, M. (2026). <p>Research progress on the effects of macrophage‑derived exosomes on muscle factors IGF‑1 and FGF‑2 mediating musculoskeletal crosstalk molecular signaling pathway on bone metabolism (Review)</p>. International Journal of Molecular Medicine, 57, 67. https://doi.org/10.3892/ijmm.2026.5738
MLA
Cui, R., Zheng, M., Hong, J., Wang, Z., Cun, Y., Gao, S., Zhu, Y., Yang, Z., Liu, M."<p>Research progress on the effects of macrophage‑derived exosomes on muscle factors IGF‑1 and FGF‑2 mediating musculoskeletal crosstalk molecular signaling pathway on bone metabolism (Review)</p>". International Journal of Molecular Medicine 57.3 (2026): 67.
Chicago
Cui, R., Zheng, M., Hong, J., Wang, Z., Cun, Y., Gao, S., Zhu, Y., Yang, Z., Liu, M."<p>Research progress on the effects of macrophage‑derived exosomes on muscle factors IGF‑1 and FGF‑2 mediating musculoskeletal crosstalk molecular signaling pathway on bone metabolism (Review)</p>". International Journal of Molecular Medicine 57, no. 3 (2026): 67. https://doi.org/10.3892/ijmm.2026.5738
Copy and paste a formatted citation
x
Spandidos Publications style
Cui R, Zheng M, Hong J, Wang Z, Cun Y, Gao S, Zhu Y, Yang Z and Liu M: <p>Research progress on the effects of macrophage‑derived exosomes on muscle factors IGF‑1 and FGF‑2 mediating musculoskeletal crosstalk molecular signaling pathway on bone metabolism (Review)</p>. Int J Mol Med 57: 67, 2026.
APA
Cui, R., Zheng, M., Hong, J., Wang, Z., Cun, Y., Gao, S. ... Liu, M. (2026). <p>Research progress on the effects of macrophage‑derived exosomes on muscle factors IGF‑1 and FGF‑2 mediating musculoskeletal crosstalk molecular signaling pathway on bone metabolism (Review)</p>. International Journal of Molecular Medicine, 57, 67. https://doi.org/10.3892/ijmm.2026.5738
MLA
Cui, R., Zheng, M., Hong, J., Wang, Z., Cun, Y., Gao, S., Zhu, Y., Yang, Z., Liu, M."<p>Research progress on the effects of macrophage‑derived exosomes on muscle factors IGF‑1 and FGF‑2 mediating musculoskeletal crosstalk molecular signaling pathway on bone metabolism (Review)</p>". International Journal of Molecular Medicine 57.3 (2026): 67.
Chicago
Cui, R., Zheng, M., Hong, J., Wang, Z., Cun, Y., Gao, S., Zhu, Y., Yang, Z., Liu, M."<p>Research progress on the effects of macrophage‑derived exosomes on muscle factors IGF‑1 and FGF‑2 mediating musculoskeletal crosstalk molecular signaling pathway on bone metabolism (Review)</p>". International Journal of Molecular Medicine 57, no. 3 (2026): 67. https://doi.org/10.3892/ijmm.2026.5738
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