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Research progress on mesenchymal stem cell‑derived exosomes in the treatment of osteoporosis induced by knee osteoarthritis (Review)

  • Authors:
    • Hai-Yan Xue
    • Xiang-Lin Shen
    • Zhi-Hua Wang
    • Hang-Chuan Bi
    • Hong-Guo Xu
    • Jie Wu
    • Ruo-Mei Cui
    • Ming-Wei Liu
  • View Affiliations / Copyright

    Affiliations: Trauma Center, The First Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650032, P.R. China, Department of Emergency, The First Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650032, P.R. China, Department of Rheumatology, The First Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650032, P.R. China, Department of Emergency, Dali Bai Autonomous Prefecture People's Hospital, Dali, Yunnan 671000, P.R. China
    Copyright: © Xue et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 160
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    Published online on: July 30, 2025
       https://doi.org/10.3892/ijmm.2025.5601
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Abstract

Knee osteoarthritis (KOA) and osteoporosis (OP) are closely related, age‑related, degenerative orthopedic conditions. Elderly patients with OP frequently develop concurrent KOA, with high co‑occurrence rates. Studies indicate that OP significantly increases KOA risk and that these conditions mutually exacerbate each other. Anti‑OP therapies show significant efficacy in KOA management, substantially delaying disease progression. Mesenchymal stem cell‑derived exosomes (MSC‑Exos) have significant therapeutic potential for both KOA and OP. These exosomes enhance chondrocyte proliferation, modulate cartilage matrix synthesis and degradation, and suppress synovial inflammation, suggesting a novel therapeutic approach for KOA. However, their OP mechanisms remain unclear but may involve disrupted bone metabolic signaling, amplified inflammation, and dysregulated intercellular communication in the bone microenvironment. The present review summarizes MSC‑Exos research advances in KOA and OP, providing a foundation for future studies and clinical applications.
View Figures

Figure 1

Relationship between exosomes and
bone formation. BM-MSCs, bone marrow-mesenchymal stem cells; RANKL,
receptor activator of nuclear factor-kappaB ligand; M-CSF,
macrophage colony-stimulating factor.

Figure 2

Source, isolation and application of
extracellular vesicles from MSCs. MSCs, mesenchymal stem cells.

Figure 3

Articular cartilage degeneration.
Healthy cartilage: Smooth, lubricin-rich, intact collagen fibers;
Knee osteoarhtritis cartilage: Fibrillated, eroded, with
fissures/ulcers; reduced lubricin.

Figure 4

Cartilage degeneration in
osteoarthritis.

Figure 5

MSC-Exos from mesenchymal stem cells
regulate multiple inflammatory pathways. MSC-Exos ameliorate
osteoporosis and osteoarthritis by regulating the following
pathways: miR-23b-3p/TAB2/NF-κB, lncRNA HIF1A-AS2/HIF-1α/VEGF,
miR-140-3p/TLR4/MyD88/NF-κB, miR-410-3p/STAT3,
circRNA_0005567/miR-203/SOCS3, and miR-181a/IKKβ/NF-κB. MSC-Exos,
mesenchymal stem cell-derived exosomes; TAB2, TGF-β-activated
kinase 1 binding protein 2; NF-κB, nuclear factor kappa B; HIF-1α,
hypoxia-inducible factor 1-alpha; VEGF, vascular endothelial growth
factor; TLR4, Toll-like receptor 4; MyD88, myeloid differentiation
primary response 88; STAT3, signal transducer and activator of
transcription 3; SOCS3, suppressor of cytokine signaling 3; IKKβ,
IκB kinase beta; MMP-13, matrix metalloproteinase-13; JAK2, Janus
kinase 2; miRNAs, microRNAs; lncRNAs, long non-coding RNAs;
circRNAs, circular RNAs. The arrows indicate the direction of
change: ↑, increased expression/activity; ↓, decreased
expression/inhibition.

Figure 6

Inflammatory regulatory mechanisms in
OP and KOA. In KOA, inflammatory mediators (IL-6, TNF-α and IL-1β)
activate NF-κB, upregulating MMPs (MMP-1/3/13) to degrade
collagen/proteoglycans; simultaneously, they activate JAK-STAT
signaling, inhibiting COL2A1/proteoglycan gene transcription,
reducing collagen/proteoglycan synthesis and causing chondrocyte
structural damage; ADAMTS upregulation mediates collagen breakdown;
ROS overproduction induces chondrocyte apoptosis; inflammation
elevates osteoblast/immune cell-derived RANKL while suppressing
OPG, promoting osteoclast differentiation/maturation and bone
resorption; macrophage/T-cell-derived IL-17/IL-23 enhances
osteoclast activity; cartilage fragments act as DAMPs, activating
TLR4 signaling; and activity and leading to increased bone
resorption. OP, osteoarthritis; KOA knee OA; MMPs, matrix
metalloproteinases; ADAMTS, a disintegrin and metalloproteinase
with thrombospondin motifs; ROS, reactive oxygen species; JAK,
Janus kinase; STAT, signal transducer and activator of
transcription; RANKL, receptor activator of nuclear factor-kappaB
ligand; TLR, Toll-like receptor; DMPS: damage-associated molecular
pattern. The arrows indicate the direction of change: ↑, increased
expression/activity; ↓, decreased expression/inhibition.

Figure 7

Osteoarthritis induces osteoporosis
through multiple regulatory pathways. During KOA, an imbalance in
joint mechanics increases local stress within the subchondral bone.
This stress stimulates osteoblasts to release the receptor
activator of RANKL, enhancing osteoclast activity and accelerating
bone resorption. Synovitis-derived factors infiltrate the
subchondral bone, inhibiting osteoblast synthesis of OPG,
increasing the RANKL/OPG ratio, further increasing osteoclast
activity, and leading to trabecular thinning. Chronic inflammation
and oxidative stress reduce OPG secretion while increasing RANKL
secretion by osteoblasts, resulting in increased bone resorption
and the coexistence of osteoporosis and osteosclerosis. Osteoclasts
secrete VEGF, prompting bone microvessels to invade the calcified
cartilage layer, disrupting calcium-phosphorus homeostasis, and
causing mixed bone loss. Inflammation increases DKK1 activity,
blocking the binding of Wnt ligands to LRP5/6. This increases
β-catenin degradation, reduces its nuclear translocation, and
inhibits osteoblast differentiation. During OP, trabecular
sparsification diminishes the shock absorption capacity,
concentrating the joint load onto the cartilage and causing
collagen fiber detachment. Impaired Wnt function disrupts bone
mineralization and calcium-phosphorus deposition, allowing vascular
invasion into the calcified cartilage layer, activating
hypertrophic chondrocytes, and increasing cartilage matrix
degradation. Imbalanced bone remodeling enhances osteoclast
activity and RANKL secretion. RANKL traverses the subchondral bone
plate, binds to chondrocytes, and activates the NF-κB pathway. This
increases MMP-13 and ADAMTS5 activity, accelerating type II
collagen degradation and proteoglycan loss. OP-induced trabecular
fractures decrease subchondral bone stiffness, causing uneven joint
surface loading and local stress concentration. This activates
Piezo1 mechanoreceptors in chondrocytes, promoting YAP nuclear
entry. This increases proinflammatory gene expression, triggers a
ROS burst, and causes mitochondrial damage. Mitochondrial
dysfunction in bone cells reduces ATP synthesis and alters
extracellular vesicle release. These vesicles carry miR-483-5p,
which is internalized by chondrocytes and inhibits SIRT3
expression. The resulting increase in oxidative stress ultimately
leads to chondrocyte pyroptosis and apoptosis. OP, osteoarthritis;
KOA knee OA; RANKL, receptor activator of nuclear factor-kappaB
ligand; OPG, osteoprotegerin; VEGF, vascular endothelial growth
factor; DKK1, Dickkopf WNT signaling pathway inhibitor 1; Wnt,
wingless-type MMTV integration site family; MMPs, matrix
metalloproteinases; ADAMTS, a disintegrin and metalloproteinase
with thrombospondin motifs; ROS, reactive oxygen species; Piezo1,
Piezo-type mechanosensitive ion channel component 1; ATP, adenosine
triphosphate; SIRT3, sirtuin 3. The arrows indicate the direction
of change: ↑, increased expression/activity; ↓, decreased
expression/inhibition.

Figure 8

Mechanisms by which mesenchymal stem
cell-derived exosomes promote joint and muscle repair. These
exosomes modulate key repair processes through the regulation of
multiple targets, including downregulating TNF-α, MMP-13, ADAMTS,
iNOS, ROS, IBA-1, NF-κB and BAX, and upregulate Runx2, ALP, OST,
HIF-1α, VEGF, aSM, CNFs, MYOG, and MyoD expression in
osteoarthritis, muscle injury, fracture, osteoporosis, spinial cord
injury, and lumbar disc degeneration. TNF-α, tumor necrosis factor
alpha; MMP-13, matrix metalloproteinase-13; ADAMTS, a disintegrin
and metalloproteinase with thrombospondin motifs; iNOS, inducible
nitric oxide synthase; ROS, reactive oxygen species; Iba-1, ionized
calcium-binding adapter molecule 1; NF-κB, nuclear factor kappa B;
BAX, BCL2-associated X protein; Runx2, Runt-related transcription
factor 2; ALP, alkaline phosphatase; OST, osteocalcin; HIF-1α,
hypoxia-inducible factor 1-alpha; VEGF, vascular endothelial growth
factor; aSM, alpha-smooth muscle actin; CNFs, centrally nucleated
fibers; MYOG, myogenin; MyoD, myogenic differentiation 1. The
arrows indicate the direction of change: ↑, increased
expression/activity; ↓, decreased expression/inhibition.

Figure 9

Regulatory mechanism of the
RANK/RANKL/OPG pathway in bone metabolism. RANKL binds to receptor
activators of RANK on osteoclast precursors, promoting osteoclast
differentiation/maturation and enhancing bone resorption through
the activation of the TRAF6, MAPK, and NF-κB pathways. OPG acts as
a decoy receptor for RANKL, inhibiting this osteoclastogenic
cascade. RANK, receptor activator of nuclear factor-kappaB; RANKL,
RANK ligand; OPG, osteoprotegerin; TRAF6, TNF receptor-associated
factor 6; NFATc1, nuclear factor of activated T cells 1; MAPK,
mitogen-activated protein kinase; NF-κB, nuclear factor κB. The
arrows indicate the direction of change: ↑, increased
expression/activity; ↓, decreased expression/inhibition.

Figure 10

Regulatory mechanism of inflammatory
mediators in bone metabolism. Inflammatory mediators disrupt bone
homeostasis through four principal mechanisms: OPG expression
combined with increased RANK/RANKL activity promotes osteoclast
differentiation and increases bone resorption; activation of the
PPARγ pathway drives the adipogenic transformation of bone marrow
mesenchymal stem cells; mitochondrial damage coupled with
cGAS-STING pathway activation induces osteoblast apoptosis; and
inhibition of Wnt/β-catenin pathway activity-mediated by
upregulated DKK1 and SOST expression-suppresses osteoblast
formation. DKK1, Dickkopf-1; SOST, sclerostin; RANKL, receptor
activator of nuclear factor-kappaB ligand; OPG, osteoprotegerin.
The arrows indicate the direction of change: ↑, increased
expression/activity; ↓, decreased expression/inhibition.

Figure 11

Regulatory mechanism of the
Wnt/β-catenin pathway in bone metabolism. Wnt proteins bind to
Frizzled receptors and low-density lipoprotein receptor-related
proteins 5/6 (LRP5/6), activating the β-catenin signaling cascade.
This pathway promotes bone marrow mesenchymal stem cell
differentiation toward osteoblasts while enhancing osteogenic
activity. The inhibitory molecules DKK1 and SOST antagonize Wnt
signaling by blocking LRP5/6 coreceptor engagement. DKK1,
Dickkopf-1; SOST, sclerostin; LRP5/6, low-density lipoprotein
receptor-related protein 5/6; GSK-3β, glycogen synthase kinase-3β.
TCF/LEF, T-cell factor/lymphoid enhancer-binding factor. The arrows
indicate the direction of change: ↑, increased expression/activity;
↓, decreased expression/inhibition.

Figure 12

Regulatory mechanism of mechanical
loading on bone metabolism. Mechanical stimulation promotes bone
formation through the activation of key pathways:
IGF-1/PI3K/Akt/mTOR signaling enhances osteoblast activity;
RANKL/RANK/OPG axis modulation favors bone formation over
resorption; the COX-2/PGE2 cascade stimulates osteogenesis; and
Wnt/β-catenin pathway activation drives osteogenic differentiation.
Conversely, mechanical unloading suppresses these pro-osteogenic
signals while upregulating bone-resorbing pathways (for example,
increasing the RANKL/OPG ratio and increasing DKK1/SOST
expression), ultimately leading to bone loss. RANKL, receptor
activator of nuclear factor-kappaB ligand; OPG, osteoprotegerin;
DKK1, Dickkopf-1; SOST, sclerostin; LRP5/6, low-density lipoprotein
receptor-related protein 5/6; COX-2, cyclooxygenase-2; PGE2,
prostaglandin E2; IGF-1, insulin-like growth factor 1; PI3K,
phosphatidylinositol 3-kinase; mTOR, mechanistic target of
rapamycin; AKT, protein kinase B; NFATc1, nuclear factor of
activated T cells 1. The arrows indicate the direction of change:
↑, increased expression/activity; ↓, decreased
expression/inhibition.
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Copy and paste a formatted citation
Spandidos Publications style
Xue H, Shen X, Wang Z, Bi H, Xu H, Wu J, Cui R and Liu M: Research progress on mesenchymal stem cell‑derived exosomes in the treatment of osteoporosis induced by knee osteoarthritis (Review). Int J Mol Med 56: 160, 2025.
APA
Xue, H., Shen, X., Wang, Z., Bi, H., Xu, H., Wu, J. ... Liu, M. (2025). Research progress on mesenchymal stem cell‑derived exosomes in the treatment of osteoporosis induced by knee osteoarthritis (Review). International Journal of Molecular Medicine, 56, 160. https://doi.org/10.3892/ijmm.2025.5601
MLA
Xue, H., Shen, X., Wang, Z., Bi, H., Xu, H., Wu, J., Cui, R., Liu, M."Research progress on mesenchymal stem cell‑derived exosomes in the treatment of osteoporosis induced by knee osteoarthritis (Review)". International Journal of Molecular Medicine 56.4 (2025): 160.
Chicago
Xue, H., Shen, X., Wang, Z., Bi, H., Xu, H., Wu, J., Cui, R., Liu, M."Research progress on mesenchymal stem cell‑derived exosomes in the treatment of osteoporosis induced by knee osteoarthritis (Review)". International Journal of Molecular Medicine 56, no. 4 (2025): 160. https://doi.org/10.3892/ijmm.2025.5601
Copy and paste a formatted citation
x
Spandidos Publications style
Xue H, Shen X, Wang Z, Bi H, Xu H, Wu J, Cui R and Liu M: Research progress on mesenchymal stem cell‑derived exosomes in the treatment of osteoporosis induced by knee osteoarthritis (Review). Int J Mol Med 56: 160, 2025.
APA
Xue, H., Shen, X., Wang, Z., Bi, H., Xu, H., Wu, J. ... Liu, M. (2025). Research progress on mesenchymal stem cell‑derived exosomes in the treatment of osteoporosis induced by knee osteoarthritis (Review). International Journal of Molecular Medicine, 56, 160. https://doi.org/10.3892/ijmm.2025.5601
MLA
Xue, H., Shen, X., Wang, Z., Bi, H., Xu, H., Wu, J., Cui, R., Liu, M."Research progress on mesenchymal stem cell‑derived exosomes in the treatment of osteoporosis induced by knee osteoarthritis (Review)". International Journal of Molecular Medicine 56.4 (2025): 160.
Chicago
Xue, H., Shen, X., Wang, Z., Bi, H., Xu, H., Wu, J., Cui, R., Liu, M."Research progress on mesenchymal stem cell‑derived exosomes in the treatment of osteoporosis induced by knee osteoarthritis (Review)". International Journal of Molecular Medicine 56, no. 4 (2025): 160. https://doi.org/10.3892/ijmm.2025.5601
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