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Current Stem Cell Research & Therapy, 2018, 13, 000-000 1
REVIEW ARTICLE
1574-888X/18 $58.00+.00 © 2018 Bentham Science Publishers
Mesenchymal Stem Cells-Derived Exosomes: A Possible Therapeutic
Strategy for Osteoporosis
Yue Li1, Daxiang Jin2,3,*, Weixing Xie2, Longfei Wen1, Weijian Chen1, Jixi Xu2, Jinyong Ding2 ,
Dongcheng Ren1 and Zenglin Xiao1
1Guangzhou University of Chinese Medicine, Guangzhou, China; 2The First Affiliated Hospital of Guangzhou Univer-
sity of Chinese Medicine, Guangzhou, China; 3Laboratory Affiliated to National Key Discipline of Orthopaedic and
Traumatology of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
A R T I C L E H I S T O R Y
Received: October 28, 2017
Revised: March 24, 2017
Accepted: March 30, 2017
DOI:
10.2174/1574888X13666180403163456
Abstract: Osteoporosis is a common age-related disorder characterized by low bone mass and deterio-
ration in bone microarchitecture, leading to increased skeletal fragility and fracture risk. The patho-
physiology of osteoporosis is multifactorial. It is related to the imbalance between osteoblasts and
osteoclasts; reduced bone mass and increased adipogenesis in the bone marrow. Moreover, angiogene-
sis, inflammatory process and miRNAs have shown effects in the formation of osteoporosis. In the
recent years, mesenchymal stem cells (MSCs) have been regarded as an excellent choice for cell-based
tissue engineering therapy of osteoporosis. Growing evidence showed that paracrine effect has been
considered as the predominant mechanism for the role of MSCs in tissue repair. Recently, many stud-
ies have proposed that MSCs-derived exosomes are effective for a variety of diseases like cancer, car-
diovascular diseases, etc. However, whether the MSCs-derived exosomes could serve as a novel thera-
peutic tool for osteoporosis has not clearly described. In this review, we summarize the MSCs-derived
exosomes and the relationship with osteogenesis, osteoclast differentiation, angiogenesis, immune
processes and miRNAs. Finally, we suggest that MSCs-derived exosomes might be a promising thera-
peutic method for osteoporosis in the future.
Keywords: MSCs, exosomes, osteoporosis, therapeutic.
1. INTRODUCTION
Osteoporosis is a common disease characterized by a sys-
temic impairment of bone mass and microarchitecture, re-
sults in increasing the propensity of fragility fractures [1].
However, the etiology of osteoporosis is complex and not
completely known so far.
The pathogenesis of osteoporosis-related to the improper
balance between the activities of osteoblasts and osteoclasts
[2]. In addition, since osteoblasts and adipocytes share a
common precursor, during the process of aging, the cell line-
age commitment of MSCs shifts to adipocyte in bone mar-
row, resulting in osteoporosis [3]. Osteoporosis and angio-
genesis are also intimately related. Accumulating evidence
from studies in animals, cells and patients suggest that the
local blood supply or decreased angiogenesis contributes to
the process of osteoporosis [4]. Inflammation is a defensive
mechanism for pathogen clearance and maintaining tissue
homeostasis. In the skeletal system, inflammation is closely
*Address correspondence to this author at the Laboratory Affiliated to Na-
tional Key Discipline of Orthopaedic and Traumatology of Chinese Medi-
cine, Guangzhou University of Chinese Medicine, Guangzhou, China; E-
mail: 18620260809@163.com
related to many bone disorders including osteoporosis [5].
MiRNAs are a class of short non-coding RNA molecules that
regulate gene expression by targeting mRNAs [6]. They are
involved in various cellular and molecular activities and
played important roles in lots of biological and pathological
processes [7]. Recently, miRNAs have been proved to play
crucial roles in the etiology of various diseases such as os-
teoporosis [8].
MSCs have been proposed as promising candidates for a
variety of therapeutic applications, such as bone, and carti-
lage regeneration, acute renal failure and neurological dis-
eases, etc. [9]. Recently, it has been identified that MSCs
exert their therapeutical activity through a paracrine effect,
mediated by the release of small particles like growth factors
[10]. Extracellular vesicles (EVs) released from MSCs are
involved in tissue regeneration and contribute to the
paracrine effect of MSCs [11].
EVs are membrane-packed vesicles and come in several
different vesicular formats [12]. Mammalian cells can release
different types of EVs. The main types include apoptotic bod-
ies, microvesicles and exosomes [13]. The largest EVs (1000–
5000 nm) are apoptotic bodies, which result from the frac-
tionation of the cellular content of cells that die by apoptosis
2 Current Stem Cell Research & Therapy, 2018, Vol. 13, No. 00 Li et al.
[14]. Microvesicles are shed directly from the cell surface
membrane and have a diameter range of 500–1000 nm [15].
Exosomes comprise one of the main subclasses of EVs and
have an endosomal origin [16]. Exosomes are small (30-
100nm) extracellular nano-sized vesicles that originate as the
internal vesicles of multivesicular bodies in many cell types
[17], such as tumor cells, T-cells, mast cells and dendritic
cells, etc. [18]. Recent findings uncovered that exosomes have
a large variety of therapeutic applications in some disorders
such as inflammatory diseases, cardiovascular diseases, meta-
bolic and neurodegenerative disorders, etc. [19].
2. PROPERTIES OF OSTEOPOROSIS AND MSCs-
DERIVED EXOSOMES
2.1. Properties of Osteoporosis
Osteoporosis is a systemic skeletal disease, characterized
by low bone mineral density (BMD) and microarchitectural
deterioration of bone tissues, with a consequent increase in
susceptibility to fracture [20]. Owing to the changes of mi-
cro-architectural in trabecular and cortical skeleton, osteopo-
rosis is manifested by fractures and enhanced skeletal fragil-
ity [21]. Hip and vertebral fractures are the most devastating
consequences of osteoporosis and are closely related to the
increased morbidity and mortality [22]. It is a worldwide
health problem with serious consequences of personal suffer-
ing and economic costs [23]. The pathophysiology of osteo-
porosis is multifactorial. Such as the imbalance between os-
teoclastic bone resorption and osteoblastic bone formation
[24]; decreased osteogenic differentiation and increased adi-
pogenic differentiation [25]. At the same time, angiogenesis
and inflammation also affect the pathogenesis of osteoporo-
sis [26, 27]. Furthermore, deregulation of miRNAs mediated
mechanisms is also becoming an important pathological fac-
tor in bone-related diseases such as osteoporosis [10].
2.2. Properties of Exosomes Derived from MSCs
In the recent years, many studies indicate that paracrine
signaling by MSCs become a potential mechanism to explain
the effects of these cells on tissue regeneration [28]. The
paracrine effects were mediated by numerous factors such as
extracellular vesicles, including exosomes. Exosomes are the
smallest subset of EVs secreted by most cell types, such as
MSCs, dendritic cells, macrophages, epithelial cells, B cells
and T cells, etc. [29]. They can also be identified in the most
bodily fluids including blood, urine, amniotic fluid, serum, etc.
[30]. Similar to the cells, exosomes are composed of a lipid
bilayer and can contain many molecular constituents of a cell,
such as proteins, miRNAs, and DNA, etc. [31]. Tetraspanins
(e.g., CD9, CD63, CD81) have been used as characteristic
markers of exosomes [32]. Currently, the most common
methods to isolate exosomes include ultracentrifugation and
immune-bead isolation [33]. We can discover via the electron
microscopy that exosomes are vesicles with deflated football
or distinctive cup shaped morphology [34] (Fig. 1) [35, 36].
2.3. Genetic Modification and the Secretion of Exosomes
from MSCs
To secrete exosomes, several cellular steps need to be
completed. Firstly, the formation of intraluminal vesicles
(ILVs) in multivesicular bodies (MVBs); secondly, transport
Fig. (1). Exosome biogenesis: exosomes are incorporated into mul-
tivesicular bodies. They could be targeted for lysosomal degrada-
tion or can be fused to cell membrane.
the MVBs to plasma membrane; third, fusion MVBs with the
plasma membrane [37]. In this process, the endosomal sort-
ing complex required for transport (ESCRT) machinery is
very important [38]. ESCRTs consist of approximately
twenty proteins that assemble into four complexes (ESCRT-
0, -I, -II and -III) with associated proteins (VPS4, VTA1,
ALIX, CHMP4C) [39]. Via the thorough RNAi screen study,
seven ESCRT proteins can affect the secretion of exosomes
[37]. Depletion ESCRT-0 proteins Hrs, TSG101 and
ESCRT-I protein STAM1 could reduce exosomes secretion
[37, 39]. Genetic modification might enhance the secretion
of exosomes. For example, knockdown of the ESCRT-III
and associated proteins VPS4B, VTA1, ALIX and CHMP4C
could increase exosome secretion [37]. The ESCRT-0,
ESCRT-I, ESCRT-III and related proteins VPS4B etc. are
important for the secretion of exosomes. So we could modify
these genes in order to regulate the secretion of exosomes
from MSCs.
MSCs secrete and synthesize exosomes that are cholesterol
rich phospholipid vesicles [40]. Compare to transplantation of
exogenous MSCs, MSCs-derived exosomes are less immuno-
genic, easier to store and deliver than MSCs [41]. Searching
for MSCs-derived exosomes is an attractive scope of the in-
vestigation because they are involved in cell-to-cell interac-
tions [42]. Recent studies demonstrate that MSCs-derived
exosomes can modulate the immune response and regenerate
tissues such as heart and nerve in vivo [43].
3. ROLES OF MSCS-DERIVED EXOSOMES IN THE
THERAPY OF OSTEOPOROSIS
3.1. MSCs-derived Exosomes and Osteogenesis
Osteogenesis is a key process responsible for the patho-
genesis of osteoporosis, promoting osteogenesis is important
for the treatments for osteoporosis [44]. Qi showed that
Mesenchymal Stem Cells-Derived Exosomes Current Stem Cell Research & Therapy, 2018, Vol. 13, No. 00 3
MSCs-derived exosomes could enhance ALP activity and
up-regulated mRNA and protein expression of osteoblast
genes in rBMSCs-OVX in vitro. At the same time, MSCs-
derived exosomes can also stimulate bone regeneration in
critical-sized calvarial defects in ovariectomized rats [45].
Furthermore, MSCs-derived exosomes can bind to matrix
proteins such as type I collagen, fibronectin and induce os-
teoblastic differentiation in vitro and in vivo [43]. Bioactive
materials such as Tricalcium Phosphate (-TCP) provide an
alternative solution for the repair of bone defects recently
[46]. However, although -TCP is osteoconductive and bio-
compatible, further improvements to osteogenesis are needed
[47]. Interestingly, when combined with the -TCP scaffolds
besides MSCs-derived exosomes, osteogenesis activity of -
TCP can be enhanced through activating the PI3K/Akt sig-
naling pathway [28, 48]. Given the osteogenic capacity of
the MSCs-derived exosomes in vitro and in vivo, the
exosomes derived from MSCs might be promising vesicles
to improve bone formation in skeletal disorders such as os-
teoporosis [49].
3.2. MSCs-derived Exosomes and Osteoclast Differentia-
tion
Normally, osteoporosis results from an imbalance of
bone resorption and bone formation, where in the net activi-
ties of the osteoclasts supersede the osteoblasts [50]. Thus,
understanding the mechanisms of MSCs-derived exosomes
regulate osteoclast formation may be useful for the treatment
of osteoporosis. MSCs release exosomes which contain func-
tional miRNAs, and then be transferred from cell-to-cell by
exosomes uptake and release, resulting in cross-cellular
gene-regulation [51]. For example, human bone MSCs-
derived exosomal miR-148a has been shown to suppress V-
maf musculoaponeurotic fibrosarcoma oncogene homolog B
(MAFB) expression and promote osteoclastogenesis [52].
The finding suggests that MSCs-derived exosomes might be
an important component to regulate osteoclast differentiation
in the treatment of osteoporosis. However, due to researches
focus on MSCs-derived exosomes influence osteoclast dif-
ferentiation are few recently, so comprehensive studies are
necessary in the future.
3.3. MSCs-derived Exosomes and Angiogenesis
Angiogenesis is the process which new vasculature
sprouts from pre-existing blood vessels [53]. Mounting evi-
dence suggests that local blood supply or decreased angio-
genesis play important roles in osteoporosis [54]. Therefore,
basic strategy for enhancing osteoporotic bone regeneration
is to promote angiogenesis [55]. Various studies have dem-
onstrated the effect of MSCs-derived exosomes on key steps
in angiogenesis [56]. Zhang J et al. found that hiPSC-MSCs-
derived exosomes could promote angiogenesis and collagen
synthesis in fibroblasts in HUVECs directly [57]. Similarly,
another study concluded that iMSCs-derived exosomes could
activate angiogenesis-related molecule expression (such as
PGF, HIF-1, TGFB1, etc.) and promote HUVECs migra-
tion and tube formation [58]. Moreover, angiogenesis plays
crucial roles in numerous physiological processes, it requires
a tight interaction between endothelial cells and their sur-
rounding environment. MSCs-derived exosomes might re-
pressed the expression of the angiogenic inhibitor delta-like
4 (DLL4) by targeting its 3 untranslated region [58]. MSCs-
derived exosomes could modulate endothelial cell angio-
genesis by promoting the formation of endothelial tip cells.
In conclusion, MSCs-derived exosomes as a pro-angiogenic
factor might be a promising candidate for the treatment of
osteoporosis [59].
3.4. MSCs-derived Exosomes and Adipogenesis
In bone marrow, osteoblasts and adipocytes share a
common precursor MSCs [60, 61]. Accumulating informa-
tion show that osteoporosis shifts the MSCs fate to favor
adipocytes over osteoblasts [62], and decrease bone mass
with marrow fat accumulation [63]. Martin et al. found that
human mesenchymal stem cells (HMSCs) derived adipo-
cytes could secrete exosomes containing adipogenic specific
mRNAs (such as leptin, PPARg, CEBPa and CEBPd tran-
scripts) and antiosteogenic miRNAs (miR30c, miR-31,
miR125a, miR-125b, miR-138) that can be transferred to
MSCs-derived osteoblasts [64]. MiR-30c and miR-31, tar-
geting osteogenic transcripts RUNX2 and Osterix [65, 66],
regulate the osteogenic differentiation. MiR-125a and miR-
125b are significantly down-regulated during osteogenic
differentiation in human adipose-derived stem cells [67].
MiR-138 modulates osteogenic differentiation of hMSCs,
overexpression of miR-138 reduced bone formation [68].
MiR-30c, miR-31, miR-125a, miR-125b and miR-138 were
selected for their capacity to inhibit osteoblast gene expres-
sion, all of them showed an increase in their expression in
the research [64]. These results probably implicated that the
miRNAs in exosomes might repress osteogenic differentia-
tion. These findings indicate that MSCs-derived exosomes
might be a target component to regulate the relationship be-
tween osteoblasts and adipocytes in the treatment of osteopo-
rosis.
3.5. MSCs-Derived Exosomes and Inflammation
The process of bone repair requires inflammatory re-
sponse, as the immune system responds to a variety of cyto-
kines that recruit and activate several cell types, like MSCs,
to promote bone formation [69]. Exosomes secreted from
MSCs have been reported to contribute to the regulation of
the immune system [70]. Dysregulated inflammation leads to
the increased bone resorption and suppressed bone formation
[71]. T cells have been identified as key regulators of osteo-
clast and osteoblast formation and activity in different dis-
eases, such as osteoporosis [72]. MSCs-derived exosomes
have an inhibitory role in the differentiation, proliferation,
and activation of T cells [73]; MSCs-derived exosomes
might regulate the immune system and influence bone me-
tabolism, suggesting potential clinical application of MSCs-
derived exosomes in cell-free therapy of osteoporosis.
3.6. MSCs-derived Exosomes and miRNAs
There are growing evidence suggesting that a number of
exosomal-containing miRNAs obtained from MSCs can
regulate bone metabolism [74]. Using isolated MSCs-derived
exosomes, a number of miRNAs (for example, miR-135b,
miR-148a, miR-199b, miR-218 and miR-221) were identi-
fied to be up-regulated during MSCs culture, while some
miRNAs (such as miR-155, miR-181a, miR-221, miR-320c
4 Current Stem Cell Research & Therapy, 2018, Vol. 13, No. 00 Li et al.
and miR-885-5p) were shown to be down-regulated [52, 75].
MiRNA let-7 was reported to enhance osteogenesis while
repressing adipogenesis of HMSCs by regulating HMGA2
[76]. MiR-199b was shown to regulate Runx2 to control the
osteogenesis [77]. MiR-218 stimulates the Wnt pathway to
promote MSCs osteogenesis [78]. MiR-135b reduced the
expression of osterix and integrin binding sialoprotein
(IBSP), suppressed MSCs osteogenic differentiation [79].
Down-regulation of miR-221 was discovered influence
Runx2 expression and trigger osteogenesis in HMSCs [52].
Therefore, future investigation will be focussed on the poten-
tial function of miRNAs derived from MSCs exosomes in
bone metabolism (Table 1) (Fig. 2) [80].
4. THE ADVANTAGE AND CHALLENGE OF MSCs-
DERIVED EXOSOMES FOR OSTEOPOROSIS
THERAPY
In the past few years, MSCs-derived exosomes have
shown exciting promise and great ability to provide thera-
peutically benefits for diseases such as rheumatoid arthritis,
osteoarthritis, etc. [81]. Use of MSCs-derived exosomes has
several potential advantages. First, their usage avoids the
transfer of cells that might have mutated or damaged DNA
[82]; Second, the vesicles are small and circulate readily
whereas MSCs are too large to circulate [82]; Thirdly,
exosomes do not contain MHCI proteins and can overcome
some disadvantages of cell transplantation therapies. Re-
searchers have shown that application to xenogeneic animals
did not induce obvious immune reactions [45].
Moreover, compared to traditional MSCs therapies,
exosomes therapies might decrease injury from MSCs trans-
plantation surgery and the possibility of favoring tumor
growth by MSCs [40]. Furthermore, exosomes have advan-
tages over the corresponding MSCs. MSCs-derived
exosomes are less complex than cells, so they are easier to
produce and also have the potential to avoid some of the
regulatory issues that face in MSCs [83]. Therefore, MSCs-
derived exosomes might represent an ideal therapeutic tool
for bone diseases like osteoporosis in the near future.
However, despite the interesting possibilities for MSCs-
derived exosomes treatment, novel therapeutic approaches
still face some challenges. First, although remarkable pro-
gress have been made in the development of exosomes isola-
tion techniques, it has also been proven that it is challenging
to rapidly and efficiently isolate exosomes. Because of the
complexity of biological samples and the heterogeneity of
exosomes themselves [84]. Second, due to the complex
structure of MSCs-derived exosomes, it might be difficult to
characterize pharmaceutically [85]. Third, the question of
which cell type to be used for exosomes derivation still re-
Table 1. MSCs-derived exosomes miRNAs and their potential effects on bone metabolism.
MiRNA Regulate Gene Effects References
let-7 HMGA2 Enhance ostegenesis/repress adipogenesis [76]
miR-199b Runx2 Control osteogenic [77]
miR-218 Wnt Enhance osteogenesis [78]
miR-135b IBSP/ Osterix Repressing osteogenesis [79]
miR-221 Runx2 Rrepressing osteogenesis [52]
miR-148a MAFB Promote osteoclastogenesis [52]
inflammation
adipogenesisangiogenesis
osteogenesisosteoclastogenesis
osteogenesis
MSC
miR-148a miR-218
miR-135b miR-221
miR30c miR -31 miR125a
miR-138
miR-125b
exo
exo
Fig. (2). MSCs-derived exosomes and the relationship with osteogenesis, osteoclast differentiation, angiogenesis, immune processes and
miRNAs.
Mesenchymal Stem Cells-Derived Exosomes Current Stem Cell Research & Therapy, 2018, Vol. 13, No. 00 5
mains to be answered [86]. Hence, the novel therapeutic ap-
proaches still need comprehensive investigation in order to
bring them into osteoporosis applications.
CONCLUSION
Osteoporosis has become a serious threat to elderly peo-
ple both at the individual and society levels. The recent find-
ings suggest that MSCs-derived exosomes might one day be
able to provide an effective therapy for bone metabolism
disease like osteoporosis. The molecular mechanisms of the
effect by MSCs-derived exosomes on osteogenesis, osteo-
clast differentiation, angiogenesis, angiogenesis and immune
processes and miRNAs have been reported here, however,
the exact mechanism still unknown and has to be studied
further. Meanwhile, considering the majority of the MSCs-
derived exosomes studies are currently on pre-clinical stage
and the conventional methods for isolating and characteriz-
ing exosomes are not effective for clinical application.
Therefore, it is important to develop a large scale of
exosomes production, as well as isolation and purification
methods. Moreover, further investigations are required to
explore specific mechanisms of generation, secretion and
action of MSCs-derived exosomes. Finally, we believe that
exosomes could be a promising new therapeutic strategy for
osteoporosis although several challenges we might face.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
This work was funded by the Science and Technology
Planning Project of Guangdong Province,
China.2016A020226007
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