Musculoskeletal crosstalk is a fundamental
physiological process that maintains human health, involving the
dynamic interaction and regulation between bone and muscle through
intricate molecular signaling mechanisms (1). Myokines such as insulin-like growth
factor-1 (IGF-1) and fibroblast growth factor-2 (FGF-2) are pivotal
in mediating this crosstalk (2).
IGF-1 regulates muscle growth and metabolism by promoting myocyte
proliferation and repair, while FGF-2 plays a critical role in
muscle regeneration and repair (3). Notably, both IGF-1 and FGF-2 not
only regulate muscle growth but also markedly influence bone
metabolism, bone density maintenance and the repair and
regeneration of bone tissue (4).
This inter-system regulatory mechanism highlights the importance of
musculoskeletal crosstalk as a critical area of research (5). Recent developments in intercellular
communication have identified macrophage-derived exosomes as
emerging signaling mediators, gaining increasing attention in the
scientific community (6).
Exosomes are small extracellular vesicles secreted by cells that
carry a range of bioactive molecules, including proteins, RNAs, and
lipids, facilitating intercellular communication and the regulation
of cellular functions and tissue physiology (7).
Macrophages regulate musculoskeletal interactions
through the secretion of exosomes (8). Exosomes derived from M1 and M2
macrophages exhibit distinct effects on musculoskeletal metabolism
(Tables I and II) (9-13). M1 macrophages, which are
pro-inflammatory, release exosomes enriched with pro-inflammatory
cytokines that can stimulate osteoclastic bone resorption,
potentially contributing to osteoporosis and bone damage. By
contrast, M2 macrophages, which possess anti-inflammatory
properties, secrete exosomes containing anti-inflammatory factors
that promote bone formation and repair. Macrophages modulate
muscle-bone signaling through the secretion of specific exosome
subtypes. Exosome-associated factors like IGF-1 and FGF-2 regulate
bone metabolic homeostasis, either promoting or inhibiting bone
remodeling.
The present review aimed to synthesize recent
insights into macrophage-derived exosomes and their role in
regulating musculoskeletal crosstalk, with a focus on their
involvement in IGF-1- and FGF-2-mediated signaling pathways. It
examined how exosomes influence the functions of these key factors
in bone metabolism, elucidated their roles in muscle and bone
homeostasis and suggested future research avenues. Additionally, it
sought to provide a theoretical framework for the development of
therapeutic strategies targeting exosomes, particularly for the
treatment of bone metabolic disorders and musculoskeletal diseases
(14).
Within the musculoskeletal system, muscle-derived
factors such as IGF-1 and FGF-2 are essential in mediating tissue
crosstalk (Table III)
(15-18). These factors coordinate the
development and repair of both bone and muscle by regulating their
bidirectional interactions. IGF-1 is a pivotal growth factor that
promotes muscle cell proliferation and differentiation while also
exerting significant regulatory effects on the skeletal system
(19). Binding to its receptor
activates the PI3K/Akt pathway, fostering muscle growth and
enhancing bone mineralization and density, thereby serving as a
critical link between bone and muscle (20). FGF-2 is a key regulator of
fibroblasts and bone marrow-derived cells, playing an indispensable
role in bone repair and muscle regeneration (21). Upon binding to fibroblast growth
factor receptors (FGFRs), FGF-2 activates downstream pathways,
including MAPK/ERK and PI3K/Akt, that promote the growth and
differentiation of osteoblasts and myocytes (22). Notably, FGF-2 supports effective
repair of muscle and bone tissues following exercise or trauma.
Beyond mechanical signals, endocrine factors also
play a vital role in musculoskeletal crosstalk (31). Muscles and bones mutually
regulate and support each other via various endocrine factors,
including IGF-1, growth hormone, sex hormones and FGF-2 (Fig. 2) (32). During growth, IGF-1 secreted by
muscles promotes muscle development and, via circulation, also
affects the skeletal system, facilitating bone formation (33). Binding to the IGF-1 receptor
(IGF-1R) in bone activates the PI3K-Akt and MAPK pathways,
regulating osteoblast proliferation and differentiation (34). Sex hormones, particularly
estrogen, are critical in regulating muscle-bone interactions
(35). Estrogen maintains bone
density and mass by promoting bone formation and inhibiting
resorption, while also enhancing musculoskeletal synergy by
regulating muscle strength and endurance (Fig. 3) (35). FGF-2, as an endocrine factor in
bone, contributes to bone repair and regulates growth and
mineralization by binding to FGFRs (Fig. 2) (36). Particularly during aging or
following fracture, FGF-2 supports bone repair by stimulating
osteoblast proliferation and differentiation (37).
As a pivotal growth factor in muscle-bone
communication, IGF-1 regulates musculoskeletal crosstalk through
multiple signaling pathways (Fig.
4) (38). Upon binding to
its receptor, IGF-1 activates the PI3K/Akt pathway, promoting
muscle fiber proliferation and repair while modulating bone cell
metabolism (39). In the
skeletal system, the PI3K/Akt pathway influences osteoblast and
osteoclast activity via downstream mTOR signaling, thus regulating
bone formation and resorption (40). Activation of PI3K/Akt leads to
Akt kinase phosphorylation, which in turn activates proteins
involved in cell growth and metabolism, promoting proliferation,
survival and differentiation (41). In bone, the PI3K/Akt pathway is
essential for bone formation by stimulating osteoblast
proliferation and differentiation, while enhancing bone matrix
mineralization (42). IGF-1
activation of this pathway improves bone density and accelerates
fracture healing, highlighting its role in bone repair (43).
FGF-2 contributes to musculoskeletal crosstalk by
promoting muscle growth and regulating bone formation and repair
through the FGFR (Fig. 5)
(44,45). In bone metabolism, FGF-2
modulates osteoblast and osteoclast functions, influencing bone
formation and resorption via the MAPK/ERK signaling pathway
(46). Research shows that FGF-2
enhances bone repair by stimulating osteoblast proliferation and
migration, accelerating new bone formation during fracture healing
(47). Additionally, FGF-2 helps
maintain bone density by balancing osteoblast and osteoclast
activity, thus reducing bone resorption (48). FGF-2 exerts a bidirectional
regulatory effect in musculoskeletal crosstalk, promoting bone
formation while inhibiting excessive bone resorption. In summary,
both IGF-1 and FGF-2 are crucial in musculoskeletal interactions,
regulating bone and muscle growth and repair through their
respective signaling pathways and coordinating the development and
repair of the musculoskeletal system through their interplay.
Exosomes are small, bilayer lipid-enclosed vesicles
secreted by cells, encompassing exosomes, microvesicles and
apoptotic bodies (7). Among
these, exosomes are the most extensively studied subtype (49). They carry a variety of cargo,
including proteins, metabolites, nucleic acids and lipids, derived
from their parent cells, exerting biological effects similar to
those of the original cells (Table
IV) (50-53). Exosomes can bind to recipient
cells through surface ligands or be internalized via paracrine
signaling and membrane fusion (such as endocytosis) (54), facilitating the transfer of
bioactive molecules and modulating recipient cell functions.
Macrophage-derived exosomes play critical roles in regulating
inflammation and influencing the progression of bone diseases, such
as osteoporosis, fractures and osteoarthritis, markedly affecting
bone metabolism and homeostasis (55-57). Research indicates that both the
composition and quantity of exosomes vary depending on the
macrophage polarization state (58-60). In recent years,
macrophage-derived exosomes have gained growing research interest,
following extensive earlier studies on exosomes from mesenchymal
stem cells (MSCs).
M1-polarized macrophages promote the release of
chemotactic and inflammatory mediators, which facilitate osteoclast
activation and debris clearance at fracture sites (61-63). MicroRNAs (miRNAs), highly
conserved non-coding RNAs, post-transcriptionally regulate gene
expression and play a key role in intercellular communication as
integral components of exosomes (64). The miRNA profiles of M1 and M2
polarized macrophages exhibit significant differences. Kang et
al (59) demonstrated that
M1 exosomes are enriched with miR-155, which inhibits the bone
morphogenetic protein (BMP) signaling pathway by downregulating
BMP2, BMP9, and Runt-related transcription factor 2 (Runx2). Given
that BMP2 is critical for osteoblast differentiation (65), its downregulation impedes bone
regeneration. Ge et al (60) reported that exosomal miR-155 from
M1 macrophages targets SOCS6, resulting in elevated p65 protein
levels. This activation of the nuclear factor
kappa-light-chain-enhancer of activated B cells (NF-κB) pathway
exacerbates inflammation. Additionally, miR-222 is highly expressed
in M1 macrophages (66). Studies
have shown that exosomal miR-222 from M1 macrophages induces
apoptosis in bone marrow mesenchymal stem cells (BMMSCs) by
inhibiting Bcl-2 expression (67-69). Yu et al (70) demonstrated that exosomal miR-98
from M1 macrophages targets DUSP1 in MC3T3-E1 cells and a
postmenopausal osteoporosis murine model, inhibiting osteogenic
differentiation. Another study showed that M1 exosomes are enriched
with miR-1246, which activates the Wnt pathway by downregulating
GSK3β and Axin2, thereby promoting cartilage inflammation and
degradation (71). These
findings were primarily validated using bioinformatics analyses,
sequencing and related methodologies. In summary, M1
macrophage-derived exosomes, which are enriched with miRNAs such as
miR-155, miR-222, miR-98 and miR-1246, modulate downstream
signaling pathways to promote inflammation and impair bone repair
both in vitro and in vivo. The specific miRNA cargo
determines the downstream signaling effects by targeting key nodes
within signaling networks. Exosomes serve as specific carriers,
enabling macrophage-derived miRNAs to function as promising
biomarkers for monitoring and regulating bone remodeling. However,
the complete repertoire of miRNAs and other cargo within macrophage
exosomes remains incompletely characterized. Further investigation
is needed to understand how macrophage polarization influences
exosomal miRNA cargo and the precise mechanisms through which these
miRNAs regulate downstream pathways. The effects of macrophage
exosomes on BMMSC differentiation have been extensively studied. He
et al (72) collected
conditioned medium (CM) from M1 macrophages and observed enhanced
BMMSC proliferation, adipogenic differentiation and extracellular
matrix deposition. Upon isolating exosomes from this CM, it was
found that M1 exosomes, but not M2 exosomes, promoted stem cell
proliferation, osteogenesis and adipogenesis. This finding was
corroborated by Xia et al (73). By contrast, Kang et al
(59) reported that co-culture
with M1 macrophages markedly reduced BMP2 and BMP9 expression in
mouse MSCs, suggesting that M1 macrophage-derived exosomes impair
the osteoinductive effects of BMPs and suppress osteogenic gene
expression in MSCs. Through exosomal communication, M1 macrophages
primarily enhance early and mid-stage osteogenesis, exerting
stronger effects on BMMSC proliferation, osteogenesis and
adipogenesis compared with M2 macrophages. These differing effects
on osteogenesis may be attributed to variations in recipient cell
sources. Experimental discrepancies could stem from multiple
factors, including macrophage maturity, co-culture conditions, the
presence of other cytokines in the CM, recipient cell lineage, and
technical differences in exosome isolation from specific
conditioned media (62,73). The balance between osteogenic and
adipogenic differentiation in BMMSCs is essential for maintaining
bone mass. Investigating the mechanisms by which M1
macrophage-derived exosomes regulate this balance in BMMSCs may
offer insights into clinical disease pathogenesis and aid in the
development of targeted therapies. Fig. 6 summarizes the regulation of bone
remodeling signaling pathways by M1 macrophage-derived
exosomes.
A critical event in bone healing is the transition
from the pro-inflammatory M1 macrophage phenotype to the
anti-inflammatory M2 phenotype (74). In the later stages of bone
healing, M2 macrophages establish an anti-inflammatory environment
that promotes osteogenesis in BMMSCs. Li et al (56) identified exosomes as key
mediators of the osteogenic process induced by M2 macrophages. BMPs
are key endogenous regulators of osteogenesis, with the loss of
BMP2 or BMP4 function leading to significant impairments in
osteogenesis. BMPs activate Smad proteins and upregulate Runx2
expression, driving MSC differentiation into osteoblasts (75,76). Using an in vivo bone
defect model, Kang et al (59) demonstrated that M2
macrophage-derived exosomes promote bone regeneration. Further
analysis revealed that M2 exosomes are enriched with miR-378a,
which enhances osteoinduction by modulating the BMP signaling
pathway, thus promoting cranial bone regeneration in mice. Studies
also indicate that exosomes from IL-4-stimulated M2 macrophages,
enriched with miRNAs such as miR-99a-5p, miR-146b-5p and
miR-378-3p, suppress inflammation by downregulating the TNF-α and
NF-κB signaling pathways in Apoe−/− mice (77). Moreover, exosomes derived from M2
macrophages promote osteogenic differentiation of BMMSCs through
miR-690, IRS-1 and TAZ, while inhibiting adipogenic differentiation
(56). Yu et al (78) reported that miR-690, enriched in
M2 macrophage-derived exosomes, upregulates osteogenic
differentiation in C2C12 myogenic progenitor cells by inhibiting
the translation of the NF-κB p65 protein. M2 macrophage-derived
exosomes are also shown to carry high levels of miR-221-5p, which
promotes tissue repair and regeneration by binding to the 3'
untranslated region (UTR) of E2F2 mRNA and negatively regulating
its expression in pancreatic ductal adenocarcinoma (79). Collectively, these studies
suggest that M2 macrophage-derived exosomes infiltrate the bone
marrow microenvironment and transfer specific miRNAs (such as
miR-378a, miR-690, miR-99a-5p) to BMMSCs, facilitating osteogenic
differentiation and fracture healing (80,81). These miRNAs likely function as
pro-osteogenic agents by modulating key pathways such as BMP
signaling to enhance osteogenesis. However, the precise roles of M2
exosome-derived miRNAs in bone formation and osteoclastogenesis
remain to be fully elucidated (82). Emerging evidence suggests that
interactions between BMMSCs and extracellular signals from M2
macrophages markedly contribute to bone formation. However, the
exact mechanisms underlying these interactions remain debated,
possibly due to differences in cell sources, co-culture conditions,
and macrophage polarization protocols. Some studies propose that CM
from M0 or M2 macrophages promotes the mineralization of BMMSCs in
the later stages of osteogenesis (83-86). By contrast, other studies report
opposing findings. For instance, Xia et al (73) found that exosomes derived from M2
macrophages inhibit BMMSC proliferation, with no significant effect
on the expression of osteogenic or adipogenic genes in BMMSCs, and
possibly even suppress chondrogenic differentiation. The regulatory
effects of M2 macrophage-derived exosomes on bone remodeling
signaling pathways are summarized in Fig. 7.
Exosomes play a pivotal role in regulating protein
synthesis and muscle regeneration by promoting satellite cell
proliferation and myofiber formation. This regulation occurs
through the delivery of myogenic growth factors such as IGF, FGF-2,
and hepatocyte growth factor (HGF) (87). Forterre et al (88) employed proteomic analysis to
identify numerous proteins associated with muscle growth and
metabolism in exosomes secreted by skeletal muscle. For example,
exosomes extracted from C2C12-derived myotubes contained key
components, such as integrin subunit β1, CD9, CD81, neural cell
adhesion molecule (NCAM), CD44 and myosin, that are potentially
crucial for myocyte differentiation. Similarly, Mobley et al
(89) demonstrated that exosomes
derived from whey protein enhance muscle protein synthesis in
vitro. Autophagy plays a critical role in maintaining muscle
mass and function; its inhibition exacerbates muscle atrophy
(90). AMPK, a central
intracellular energy sensor, alleviates sarcopenia (SP) symptoms
and mitochondrial dysfunction (91). Chen et al (92) discovered that exosomes from MSCs
ameliorate muscle atrophy by enhancing AMPK/ULK1-mediated
autophagy. Guescini et al (93) observed that exosomal miR-133b and
miR-181a-5p are rapidly released into the bloodstream
post-exercise, promoting muscle regeneration. This mechanism may
partially explain how exercise mitigates SP. Furthermore,
Chaturvedi et al (94)
demonstrated in animal models that exercise-induced exosomes
promote skeletal muscle regeneration through the upregulation of
miR-9b and miR-29.
Additionally, extracellular vesicles from M1
macrophages can polarize recipient macrophages toward an M2-like
phenotype, thereby altering skeletal muscle homeostasis under
high-glucose conditions. Collectively, these findings highlight the
roles of both M1- and M2-derived macrophage exosomes in regulating
SP.
Exosomes serve as critical messengers in muscle-bone
crosstalk, enabling skeletal muscles to influence bone activity
through EV-mediated communication. This exosome-mediated
communication between skeletal muscle cells occurs via autocrine,
paracrine, or endocrine pathways (95-98). Exosomes derived from C2C12
myoblasts promote the osteogenic differentiation of MC3T3-E1
preosteoblasts, likely mediated by the upregulation of miR-27a-3p
in recipient cells. This miRNA suppresses specific target genes and
activates β-catenin signaling, thereby enhancing osteogenesis
(99). Additionally, exosomes
from C2C12 myoblasts enhance Wnt/β-catenin signaling in
TOPflash-MLOY4 osteocyte-like cells, promoting cell survival and
providing protection against apoptosis and oxidative stress. This
protective effect is likely due to exosomes-mediated inactivation
of Wnt inhibitors, such as SOST, DKK2, and SFRP2 (100). Li et al (101) showed that myoblast-derived
exosomes carry Prrx2, which activates miR22HG transcription,
promoting osteogenic differentiation of BMMSCs via the YAP pathway
and miR-128. Furthermore, CXCR4, present on exosomes produced by
mouse fibroblasts, targets these vesicles to the bone marrow, where
miR-188-containing exosomes fuse with lipids to form hybrid
nanoparticles. These nanoparticles then release miR-188 in a
targeted manner, inhibiting adipogenesis and promoting BMMSC
differentiation into osteoblasts (102). Regarding the influence of bone
cell-derived exosomes on skeletal muscle, long non-coding RNAs
(lncRNAs) are critical. For example, Zheng et al (103) found that osteoblasts induce
myogenic differentiation of C2C12 myoblasts via exosomal lncRNAs,
specifically TUG1 and DANCR. Toita et al (104) demonstrated that collagen
patches releasing phosphatidylserine-containing liposomes promote
M1-to-M2 macrophage polarization, facilitating concurrent bone and
muscle tissue healing. Transcriptome analysis via next-generation
sequencing revealed that M1 macrophage secretory products inhibit
the differentiation of preosteoblasts and myoblasts, while M2
macrophage secretory products promote it. This highlights the
importance of timely M1-to-M2 polarization for effective tissue
regeneration. As shown in Fig.
8, macrophages, particularly the M2 phenotype, release exosomes
carrying the transcription factor C/EBPβ. This factor promotes
skeletal muscle cell proliferation and differentiation via the
PPARγ signaling pathway (105).
Depletion of macrophage exosomes containing C/EBPβ markedly
inhibits ALP activity in muscle cells and reduces the expression of
myogenic markers (such as MyoD and MyoG), delaying muscle injury
repair (105). M2
macrophage-derived exosomes suppress M1 macrophage activity by
delivering anti-inflammatory factors, such as IL-10 and TGF-β,
while mitigating the damaging effects of pro-inflammatory factors
like TNF-α and IL-6 on muscle fibers. They also promote the
directed differentiation of stem cells into myocytes (106). Additionally, M2 macrophage
exosomes activate the PI3K/AKT pathway, facilitating the shift from
M1 to M2 polarization. This process leads to reduced inflammatory
cytokine levels, improved bone immune microenvironment and enhanced
osteoblast differentiation and angiogenesis (107). Under mechanical stimulation,
macrophages increase exosome secretion. These exosomes carry the
UCHL3 protein, which enhances the osteogenic potential of BMMSCs
and drives callus formation through the SMAD1 signaling pathway
(108). Exosome-encapsulated
miRNAs, including miR-21 and miR-148a, inhibit osteogenic
inhibitors like PTEN and upregulate RUNX2 and osterix (106). In osteosarcoma models, exosomes
coordinate osteoclast and osteoblast activity by transmitting
Wnt/β-catenin signals, contributing to the maintenance of bone
homeostasis (106). These
findings highlight the critical role of macrophage-derived exosomes
in regulating the proliferation and repair of both bone and muscle
tissues, modulating muscle-bone crosstalk and enhancing tissue
regeneration.
Exosomes function as essential intercellular
signaling vehicles, transporting a variety of biologically active
molecules, including miRNAs, mRNAs, proteins and lipids (109). These components regulate bone
metabolism by modulating signaling pathways in target cells
(110). Notably, miRNAs within
macrophage-derived exosomes are recognized as key regulatory
factors (111). Research
indicates that macrophage-derived exosomal miRNAs influence bone
metabolism indirectly by regulating key signaling molecules such as
IGF-1 and FGF-2 (Figs. 9 and
10) (112). miRNAs modulate gene expression
by binding to target mRNAs, resulting in translational repression
or mRNA degradation (113). In
musculoskeletal crosstalk, exosomal miRNAs from macrophages play
pivotal roles in the regulation of IGF-1, FGF-2 and other signaling
pathways (Figs. 9 and 10) (114). For instance, macrophage-derived
exosomal miR-21 promotes IGF-1 signaling by targeting inhibitory
molecules within the PI3K-Akt pathway, thereby enhancing bone
formation (115). Similarly,
macrophage-derived exosomal miR-29 boosts osteoblast function,
promoting bone matrix synthesis and mineralization through the
regulation of FGF-2 expression (116). By contrast, M1 exosomal miR-155
directly inhibits IGF-1R and downstream PI3K/Akt signaling,
diminishing osteoblast differentiation (117). Additionally, M1 exosomal
miR-143 exacerbates insulin-resistant muscle atrophy by inhibiting
IRS-1 and obstructing the pro-muscle protein synthesis effect of
IGF-1 (118). Thus,
macrophage-derived exosomes regulate musculoskeletal crosstalk via
exosomal miRNAs during IGF-1 and FGF-2 signaling, revealing a novel
molecular mechanism (Figs. 9 and
10).
Exosomes carry a diverse array of cargo molecules
that regulate bone and muscle metabolism through interactions with
receptors on the surface of musculoskeletal cells (119). Signal transduction by IGF-1 and
FGF-2 in bone metabolism is initiated when these factors bind to
their specific cell surface receptors (120). Macrophage-derived exosomes can
modulate bone metabolism by transporting receptors or receptor
ligands that facilitate the binding of signaling factors to their
target cells (121). Exosomal
ligands for IGF-1R and FGFR directly bind to their corresponding
receptors on bone or muscle cells, triggering signal transduction
(122). Upon IGF-1 binding,
IGF-1R activates intracellular signaling cascades, primarily via
the PI3K/Akt and MAPK pathways, to regulate bone and muscle growth
and repair (123,124). Macrophage-derived exosomes can
deliver IGF-1R or its ligands, thereby enhancing IGF-1 signaling to
promote bone formation and muscle repair (Fig. 9) (125). Similarly, FGF-2 binding to FGFR
initiates signaling cascades that regulate the proliferation and
differentiation of bone marrow stromal cells and osteoblasts
(126). FGF-2 targets
sclerostin in bone and myostatin in skeletal muscle to counteract
the harmful effects of glucocorticoids on musculoskeletal
degradation (127). The
exosome-mediated interaction between FGF-2 and FGFR enhances bone
repair and plays a pivotal role in musculoskeletal crosstalk
(Fig. 10) (128). In summary, macrophage-derived
exosomes facilitate signal transduction and regulate bone
metabolism by transporting receptors (such as IGF-1R, FGFR) and
their ligands, strengthening bone formation and repair, and
promoting musculoskeletal crosstalk.
Osteoblast proliferation, differentiation and
mineralization are essential processes in bone metabolism,
regulated by macrophage-derived exosomes through various mechanisms
(129). During osteogenesis,
active molecules such as miRNAs and proteins facilitate osteoblast
proliferation, differentiation, and mineralization (130). Exosomal miRNAs secreted by
macrophages, including miR-21 and miR-29, can activate the PI3K/Akt
and Wnt/β-catenin signaling pathways in osteoblasts, promoting
their proliferation and differentiation (131); M1 macrophage-derived exosomes
aggravate bone loss in postmenopausal osteoporosis via a
miR-98/dual specificity phosphatase 1 (Dusp1)/c-Jun N-terminal
kinase (JNK) axis (132); M2
macrophagy-derived exosomal miRNA-26a-5p induces osteogenic
differentiation of bone mesenchymal stem cells (133); Exosomal miR-486-5p secreted by
M2 macrophage influences the differentiation potential of bone
marrow mesenchymal stem cells and osteoporosis (134). These miRNAs enhance osteoblast
differentiation and bone matrix deposition by inhibiting negative
regulatory factors and activating key transcription factors, such
as Runx2 and Osterix (135,136). Additionally, exosomal proteins
such as TGF-β and BMPs support mineralization by regulating
osteoblast proliferation and differentiation (137). TGF-β activates the Smad
signaling pathway through receptor binding, enhancing osteoblast
mineralization (138). BMPs, on
the other hand, activate the Smad1/5/8 pathway, which promotes
osteoblast differentiation and stimulates bone matrix synthesis and
mineralization (139), as
summarized in Table V (140-143).
The function of osteoblasts is further regulated by
a series of transcription factors, with Runx2 and Osterix being two
critical regulators of osteogenic differentiation (144). Macrophage-derived exosomes
influence osteoblast function by modulating the expression of these
transcription factors (145,146). Exosomes secreted by macrophages
carry specific miRNAs, such as miR-124-3p and miR-146a, which
regulate Runx2 and Osterix expression (147,148). For example, miR-224-5p targets
the 3' UTR of Runx2, preventing its degradation and thereby
promoting osteoblast differentiation (149); miR-6879-5p carried by M2
macrophage-derived exosomes increases Runx2 expression and promotes
osteogenic differentiation and aerobic glycolysis in human
periodontal ligament stem cells (hPDLSCs) via modulating
TRIM26-mediated ubiquitination of pyruvate kinase M (PKM) (150); M2 macrophage exosomes carrying
miRNA-26a-5p can induce osteogenic differentiation of bone
marrow-derived stem cells to inhibit lipogenic differentiation by
promoting the expression of RUNX-2 (151). Additionally, miR-664-3p
promotes osteoblast differentiation and mineralization by
regulating Osterix expression (152). As a key transcription factor
downstream of Runx2, Osterix drives bone matrix formation and
mineralization (147). As well
as miRNAs, proteins such as TGF-β and BMP in macrophage-derived
exosomes also promote osteoblast differentiation by modulating
Runx2 and Osterix expression (153,154). TGF-β enhances Runx2 expression
through the activation of the Smad2/3 signaling pathway, promoting
osteoblast differentiation (136). BMPs stimulate Osterix
expression and enhance bone matrix deposition and mineralization
via the Smad1/5/8 signaling pathway (155).
The formation and activation of osteoclasts, the
primary cells responsible for bone resorption, are essential
processes in bone metabolism (156). Macrophage-derived exosomes
contribute to bone resorption and regulate bone metabolism by
modulating osteoclast formation and activation (157). Osteoclast formation is governed
by various factors, including Receptor Activator of Nuclear Factor
κ-B Ligand (RANKL) and Macrophage Colony-Stimulating Factor (M-CSF)
(158,159). Macrophage-derived exosomes
promote osteoclast formation by carrying RANKL and M-CSF (160,161). Specifically, exosomal RANKL
binds to the RANK receptor on osteoclasts, activating the NF-κB and
MAPK signaling pathways to drive osteoclast formation and
activation (162,163). By binding to its receptor
c-Fms, M-CSF activates the PI3K/Akt signaling pathway, accelerating
osteoclast differentiation (164). Additionally, macrophage-derived
exosomes can further promote osteoclast formation by modulating
other cytokines, such as IL-1 and TNF-α, which enhance RANKL
expression through the activation of the NF-κB signaling pathway,
thereby promoting osteoclast activation (57). Consequently, macrophage-derived
exosomes facilitate bone resorption by carrying RANKL, M-CSF, and
other factors that regulate osteoclast formation and
activation.
IGF-1 and FGF-2 play pivotal roles in both bone and
muscle metabolism. Osteoporosis, often accompanied by SP, is a
condition that involves diminished bone density and function,
alongside muscle degradation. Macrophage-derived extracellular
vesicles have been shown to improve both osteoporosis and SP by
regulating IGF-1 and FGF-2 signaling.
Osteoporosis is characterized by reduced bone
density, deterioration of bone microarchitecture and increased
fracture risk, primarily affecting older adults (172). Recent studies suggest that
osteoporosis is not only associated with abnormal bone metabolism
but also with impaired muscle function (Figs. 11 and 12), highlighting the significance of
musculoskeletal crosstalk in the pathogenesis of osteoporosis
(Figs. 11 and 12) (172,173). In osteoporosis, the functions
of macrophage-derived exosomes, IGF-1, and FGF-2 are markedly
altered. Macrophages, as key immune cells (174,175), contribute to bone metabolism
through exosomes that transport a variety of signaling molecules,
including cytokines, miRNAs, and proteins (176). Impaired macrophage function in
patients with osteoporosis alters the signaling molecule profile
within exosomes (177). These
changes may accelerate bone loss by disrupting the balance between
bone resorption and formation through various signaling pathways.
IGF-1 plays a central role in bone metabolism by regulating bone
formation, primarily through the PI3K/Akt and MAPK signaling
pathways (178,179).
The primary manifestations of osteoporosis, bone
loss and reduced bone strength, are influenced by the interaction
of macrophage-derived exosomes, IGF-1 and FGF-2 (180). These components synergistically
regulate bone formation and resorption, thereby affecting bone mass
(181). Exosomal miRNAs, such
as miR-21 and miR-146a, derived from macrophages, can promote
osteoclast differentiation and activity by modulating the
RANKL/RANK pathway, leading to excessive bone resorption (182). Additionally, exosomal protein
factors such as TGF-β and BMP further inhibit bone formation by
regulating osteoblast function (183). In osteoporosis, IGF-1, a key
osteogenic factor, is often underexpressed, impairing osteogenesis
and leading to reduced bone formation (184). Similarly, FGF-2 signaling is
suppressed in osteoporosis, contributing to further bone density
loss (185). This disruption in
signaling between IGF-1 and FGF-2 exacerbates bone loss. Exosomes
carrying RANKL and TGF-β promote osteoclastogenesis and bone
resorption (186), while the
deficiency of IGF-1 and FGF-2 signaling further impairs bone
formation. Disruption of this delicate musculoskeletal crosstalk
and the associated molecular pathways plays a pivotal role in the
pathogenesis of osteoporosis (187).
SP refers to the age-related progressive loss of
skeletal muscle mass and function (188). It is not only a natural part of
aging but is also closely linked to various diseases and
pathological conditions. The relationship between SP and abnormal
bone metabolism has gained considerable attention in recent years.
Muscle atrophy and bone metabolism interact bidirectionally,
forming a critical regulatory mechanism for maintaining bone health
(189). As depicted in Fig. 13, the onset of SP is often
accompanied by decreased bone density and altered bone metabolism.
Muscle atrophy influences bone metabolism through multiple
mechanisms (190). It reduces
muscle strength and load-bearing capacity, thereby diminishing
mechanical stress on bones. This reduction in mechanical
stimulation leads to increased bone resorption and decreased bone
formation (190). Additionally,
SP affects bone metabolism through the secretion of inflammatory
factors, such as IL-6 and TNF-α (191). These inflammatory mediators
activate osteoclast signaling pathways, enhancing bone resorption
and consequently reducing bone density (192). Moreover, endocrine dysfunction
linked to SP plays a significant role in abnormal bone metabolism.
Muscle atrophy leads to reduced secretion of myokines, such as
IGF-1 and FGF-2, impairing bone formation.
Macrophage-derived exosomes, along with IGF-1 and
FGF-2, play pivotal roles in the bone metabolism abnormalities
associated with SP (193,194). Macrophages, as key immune
cells, secrete exosomes carrying a range of cytokines and miRNAs
that are essential for musculoskeletal crosstalk (195). The miRNAs, cytokines and growth
factors transported by macrophage exosomes affect all aspects of
bone metabolism (196). For
example, macrophage-derived exosomes promote osteoclast formation
and activity by delivering miRNAs (such as miR-146a and miR-21),
thus enhancing bone resorption (197). These exosomal miRNAs can
activate specific signaling pathways by binding to receptors on
bone cells, influencing the pathogenesis of conditions such as
osteoporosis and bone loss (197). Moreover, the roles of IGF-1 and
FGF-2 in SP are particularly important (198). IGF-1 is well-established as
essential for muscle tissue, promoting not only muscle growth and
repair but also bone matrix formation by enhancing osteoblast
function (199). However,
circulating IGF-1 levels are often reduced in patients with SP,
contributing to bone metabolism disorders. Similarly, FGF-2 is
another key osteogenic factor involved in SP.
Exosome isolation from macrophages typically
involves techniques such as ultracentrifugation, size exclusion
chromatography, immunoaffinity capture, and kit-based methods.
Identification techniques include transmission electron microscopy
(TEM), nanoparticle tracking analysis (NTA), western blotting (WB)
and nanoflow cytometry. Each method offers distinct advantages and
limitations. In muscle and bone metabolism experiments, in
vitro methods include osteoblast differentiation assays,
osteoclast inhibition tests, muscle cell differentiation
experiments, and muscle metabolism studies. In vivo
approaches include osteoporosis models, fracture healing models,
and SP models.
Exosomes are nanoscale extracellular vesicles
(30-150 nm in diameter) secreted by cells and are widely
distributed in various body fluids (200). The isolation and purification
of exosomes from macrophages is a critical step in studying
musculoskeletal crosstalk and its impact on bone metabolism
(201). Conventional methods
for exosome isolation primarily include ultracentrifugation and
commercial kit-based approaches (201). Ultracentrifugation is regarded
as the gold-standard technique for exosome separation, relying on
density-based differentiation to isolate exosomes from other
cellular components (202).
This process involves removing cellular debris through low-speed
centrifugation, followed by high-speed ultracentrifugation to
pellet exosomes (202).
Although this method is widely adopted, straightforward and
cost-effective, it is time-consuming and requires significant
technical expertise (202).
Despite these limitations, ultracentrifugation remains the most
commonly used method due to its high yield and efficiency in
exosome collection (203). By
contrast, commercial kit-based methods use reagents for exosome
separation, often employing immunomagnetic beads or affinity
capture technologies (204).
These kits are convenient, easy to use, and improve exosome purity
markedly (204). However, they
tend to be expensive and may exhibit lower extraction efficiency,
especially in samples with high levels of contaminating cellular
material (204). A comparative
summary of these techniques is provided in Tables VI and VII (205-216).
Investigating the impact of macrophage-derived
exosomes, IGF-1, and FGF-2 on musculoskeletal crosstalk requires
the establishment of a co-culture system that incorporates both
muscle cells and osteocytes. Commonly used bone cell models include
the MC3T3-E1 murine pre-osteoblastic cell line and the RAW264.7
murine monocytic cell line (222). These cell lines exhibit high
proliferative and differentiation capacities, making them ideal for
in vitro investigations (222). For muscle cell models, the
C2C12 mouse myoblast cell line and the L6 rat skeletal muscle cell
line are frequently used (223). The C2C12 cell line, in
particular, differentiates into myotubes under appropriate
conditions and is widely employed in muscle biology research
(224). This co-culture model
simulates the in vivo physiological environment and serves
as a robust platform for studying muscle-bone interactions.
Co-culture systems are typically established using either Transwell
inserts or direct contact methods. In the Transwell system, a
porous membrane (typically 0.4 μm) separates the cell types,
enabling paracrine signaling via soluble factors while preventing
direct cell-cell contact (225). This setup allows for precise
control over the transfer of soluble factors between cell
compartments (225). However,
direct contact co-culture more accurately replicates the physical
interactions and signaling processes, including mechanical
stimulation, between muscle and bone cells (226).
Experimental designs investigating the interactions
between macrophage-derived exosomes, IGF-1, and FGF-2 typically
involve four key components: Exosome isolation and processing, gene
interference, protein expression analysis and functional assays. A
critical step in this experimental design is the processing of
exosomes, typically secreted by macrophage cell lines such as
RAW264.7. Exosomes from M1 macrophages are enriched with
pro-inflammatory factors, while exosomes derived from M2
macrophages carry anti-inflammatory and tissue-repair factors
(227). In experiments,
exosomes isolated from macrophage cell lines (such as RAW264.7) are
introduced into muscle and bone cell co-culture systems to assess
their effects on cellular proliferation, differentiation, and
mineralization (228). To
determine the specific influence of IGF-1 and FGF-2, their
functions can be inhibited using specific antagonists or gene
interference techniques, such as siRNA, to confirm their roles in
mediating musculoskeletal crosstalk. Additionally, techniques such
as WB and qPCR can be employed to analyze how M1 and M2 exosomes
regulate IGF-1 and FGF-2 expression, as well as the activity of
their downstream signaling pathways, including PI3K/Akt and MAPK
(229). Functional assays, such
as osteogenic evaluation via Alizarin Red staining and osteoclastic
activity assessment using TRAP staining, can be used to verify the
effects of exosomes on bone cell function (230). Collectively, this experimental
approach provides a framework for elucidating the complex
interactions and regulatory mechanisms involving M1- and
M2-macrophage-derived exosomes, IGF-1, and FGF-2 in bone
metabolism.
In animal studies, various intervention strategies
are employed to investigate the effects of macrophage-derived
exosomes (from M1 or M2 phenotypes), IGF-1, FGF-2 and related
factors on bone metabolism. These agents, such as M1- or M2-derived
exosomes, IGF-1 and FGF-2, are typically administered through local
injection or systemic intravenous delivery. Researchers establish
multiple experimental groups, including those treated with
M1-derived exosomes, M2-derived exosomes, IGF-1, FGF-2, and vehicle
controls, to enable direct comparison of the specific effects of
each intervention on bone metabolism. Standard detection endpoints
include bone densitometry such as dual-energy X-ray absorptiometry,
histological analysis of bone tissue (such as hematoxylin and eosin
[H&E] staining, Alizarin Red staining) and serum biomarkers of
bone metabolism (such as osteocalcin, C-terminal telopeptide of
type I collagen, bone-specific alkaline phosphatase) (246). These parameters offer a
comprehensive evaluation of bone metabolism, allowing for an
in-depth assessment of the effects mediated by M1 and M2
macrophage-derived exosomes. Collectively, these animal experiments
shed light on how M1 and M2 macrophage-derived exosomes modulate
IGF-1 and FGF-2 signaling within the musculoskeletal crosstalk
network, influencing osteocyte proliferation, differentiation and
mineralization. These findings provide a foundation for developing
novel therapeutic strategies.
Estrogen influences bone and muscle metabolism
differently in males and females (Table IX) (261-271). The decline in estrogen levels
is the primary cause of postmenopausal osteoporosis in women
(240), leading to reduced bone
mass, muscle atrophy and an increased risk of falls and fractures
(240). SP often coexists with
osteoporosis, resulting in osteosarcopenia (272). While male androgens
predominantly regulate muscle and bone metabolism, estrogen remains
crucial for maintaining bone strength and muscle metabolic
adaptability (267). Further
studies indicate that in obesity or infection models, male
macrophages tend to be M1 polarized, with their exosomes rich in
pro-inflammatory miRNAs (such as miR-155) that inhibit the insulin
signaling pathway (273). By
contrast, macrophage extracellular vesicles in female models carry
higher levels of anti-inflammatory factors (such as miR-125a-5p),
enhancing tissue repair (274).
The decrease in estrogen levels in postmenopausal women leads to an
M1/M2 imbalance, accelerating bone loss (with osteoporosis rates
twice as high as in men) (274). In males, high testosterone
levels are positively associated with muscle mass (275). However, obese males exhibit
higher expression of miR-155 in macrophage exosomes from adipose
tissue, which increases the risk of insulin resistance (276). M2 macrophage exosomes mediate
the polarization of macrophages into anti-inflammatory phenotypes
in female models, accelerating muscle regeneration (277). These findings suggest that
estrogen exerts distinct effects on bone and muscle metabolism
across sexes, leading to different regulatory mechanisms of
macrophage exosomes in estrogen-induced muscle-bone metabolism
abnormalities, influenced by sex-specific factors.
Although RAB-GTPase-modified exosomes (RAB-EXOs),
engineered via click chemistry, can target bone tissue in complex
in vivo environments, their targeting and enrichment
efficiencies remain suboptimal (278). Drug concentrations at sites of
deep-seated bone infections, such as osteomyelitis, are often
insufficient and systemic administration can result in off-target
effects and potential adverse reactions. Studies show that
intravenously injected exosomes are primarily taken up by the
liver, skeletal muscle and adipose tissue (279-281). Enhancing exosome enrichment at
specific bone lesion sites remains a critical challenge that needs
urgent resolution (282).
Exosomes derived from macrophages of different sources and
polarization states exhibit significant differences in composition
and biological function. Exosomes from M1 and M2 macrophages can
exert opposing biological effects, and this heterogeneity presents
a considerable challenge for developing standardized therapies. One
study demonstrated that exosomes secreted by adipose tissue
macrophages in obese mice promote insulin resistance (283), whereas those from M2
macrophages improve insulin sensitivity (284). Ensuring batch-to-batch
consistency and functional stability of therapeutic exosomes is a
major challenge, as is overcoming technical bottlenecks in their
large-scale production. Exosomes isolated from 20-25 lean mice are
needed to treat one obese mouse, yielding too little for clinical
translation. Although in vitro induction of M2 macrophages
can partially address source limitations, optimization of culture
conditions, purification protocols and storage stability remains
necessary. The use of composite technologies with carrier materials
(such as hydrogels) also faces challenges in large-scale
production. While specific miRNAs, such as miR-690, mediate the
insulin-sensitizing effects of M2 macrophage-derived exosomes
(284) and the PI3K/AKT pathway
regulates macrophage polarization, significant knowledge gaps
remain regarding their application in treating musculoskeletal
tissues. The full molecular network underlying bone metabolic
diseases is not yet fully understood (285). Key questions concerning
exosomal release kinetics, interactions with host cells, and
long-term effects of exosomal cargo require further in-depth
investigation. This lack of knowledge hinders the precise design
and optimization of therapeutic regimens.
Exosomes are nanoscale extracellular vesicles with
diverse bioactivities; however, their long-term safety profile
remains incompletely characterized. Although animal studies have
shown that RAB-EXOs induce no adverse reactions within a 28-day
period in osteomyelitis treatment (286), their immunogenicity, potential
toxicity and the risk of off-target effects in human applications
require systematic evaluation. This is especially important for
patients with metabolic diseases, as exosome-based therapies may
have complex and unpredictable effects on systemic metabolic
networks. Consequently, a comprehensive safety evaluation framework
and robust risk mitigation strategies must be established.
In conclusion, exosomes derived from M1 and M2
macrophages play pivotal roles in muscle-bone crosstalk,
particularly within molecular signaling pathways mediated by
myokines such as IGF-1 and FGF-2. These factors are essential
regulators of muscle growth and bone metabolism, promoting muscle
cell proliferation and differentiation while influencing bone cell
function through various signaling pathways. Their roles extend
beyond direct regulation of local cellular behavior, modulating
bone metabolic homeostasis via macrophage-derived exosomes. Ongoing
research continues to uncover the complex mechanisms through which
M1 and M2 macrophage-derived exosomes affect bone metabolism.
Exosomes facilitate intercellular communication by transporting
bioactive molecules (such as proteins, RNAs and lipids), regulating
bone tissue formation and remodeling. Specifically, exosomes
secreted by M1 and M2 macrophages can modulate bone density and
strength by influencing osteoblast and osteoclast activity,
promoting bone health and aiding in repair. These findings provide
valuable insights into the intricate mechanisms governing bone
metabolism and lay the groundwork for developing new therapeutic
strategies.
To address current challenges, researchers are
exploring several strategies, including engineering targeted
modification technologies to enhance exosomal tissue specificity,
establishing standardized production and quality control protocols,
applying multi-omics approaches to clarify mechanisms of action and
developing smart, responsive carrier systems to improve delivery
efficiency. Innovative solutions, such as M2 macrophage
exosome-hydrogel composites, show promise for bone regeneration
therapy, but further preclinical and clinical studies are essential
to evaluate their safety and efficacy. Interdisciplinary
collaboration will be vital in advancing this field. Further
investigation into the mechanisms of M1 and M2 macrophage-derived
exosomes is expected to lead to more effective interventions for
bone-related diseases, including osteoporosis and fracture
repair.
Not applicable.
Conceptualization was by RMC, MZ, and JBH. Data
curation was by ZXW and YFC. Funding acquisition was secured by
MWL. Investigation was by SJG and YLZ. Project administration was
performed by YLZ. Software management was overseen by ZBY. Figures 1-13 were prepared by MWL and RMC.
Supervision was led by MWL. Validation was performed by RMC and
visualization was by MZ. The original draft of the manuscript was
written by MWL, who contributed to the review and editing. Data
authentication is not applicable. All authors read and approved the
final manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
The present study was supported by the Union Foundation of
Yunnan Provincial Science and Technology Department and Kunming
Medical University (grant no. 202201AY070001-091), Yunnan Province
Clinical Center for Skin Immune Diseases (grant no.
YWLCYXZX2023300076) and the Natural Science Foundation of China
(grant no. 81960350).
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