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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_6035_Библиотеки_им_академика_М_И_Перельмана.pdf
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FIGURE 18.4 Icariin flavonoids act upon preosteoblast and inhibit the regulation of different markers related
to osteoblast and osteoclast activity.
⏎
Icariin induces the terminal differential marker ALP and Col I and mineralization of
osteoblast, which nally helps in bone remodeling (Ma et al., 2014). In vivo rat model
(glucocorticoid-induced osteoporosis) showed increase in bone mass with icariin (125
mg/kg daily for 12 weeks) as compared to the established drug alendronate, where
ALP was signicantly increased and the antiapoptotic effect of icariin also observed in
osteocytes (Feng et al., 2013). It also shows an inhibitory effect on osteoclast by p38,
extracellular signal-regulated kinases (ERK) NF-kB, and c-Jun N-terminal kinase (JNK)
signaling pathway at 10
−8
M dosage in 8-month-old Institute of Cancer Research mice
(Hsieh et al., 2011).
Another important isoavonoid ikarisoside A from E. koreanum showed antioxidant
and anti-inammatory properties in LPS-stimulated bone marrow-derived macrophage
precursor cells and in RAW 264.7 cells. Ikarisoside made better osteointegration in the
trabecular and cortical bone in the OVX mouse model. It suppressed osteoclast differentiation and resorption through RANKL-induced TRAF6-MAPK-p38-NFATc1 cascade
(Chen et al., 2023). It attenuated osteoclast differentiation by suppressing the p38-MAPK
pathway without affecting JNK and ERK signaling. In the RANKL family, it suppressed
NFATc1 (transcription factor) in mRNA and protein levels, which is denoted as the main
transcription factor for osteoclast differentiation (Figure 18.5).
464
FIGURE 18.5 General molecular mechanism of action of isoflavonoids in the activity of osteoclasts and
osteoblasts.
⏎
This family comprises soybean, scientifically known as Glycine max L, and mainly
contains daidzein, biochanin A, and genistein supplemental proteins, which are ef fective in
mineral depletion on bone mass. The predominant amount of phytoestrogen in soybean is
involved in bone metabolism. Histological findings (in vivo) suggested that the BMD, BV,
osteogenic markers in serum, and bone formation-related molecules increase by the effect
of phytoestrogens in postmenopausal women (Baek et al., 2023). The mixture of Cervus
elaphus sibiricus and Glycine max L. application in the OVX mouse model resulted in the
downregulation of TRAP activity in the femur along with Ca and osteocalcin (OC). These
will trigger the regulation of BMP and MAPK pathways (Baek et al., 2023).
The application of another isoavonoid called genistein from soy plant (Fukutake
et al., 1996) resulted in the modulation of B-lymphopoiesis and inhibited bone degradation
(Zhai et al., 2017). The antiosteoporotic property of the avonoid comes from enzymatic
inhibition of protein kinase and activation of the ES type I receptor, which makes it more
effective against osteoporosis than other avonoids. The fruit of Psoralea corylifolia plant
is used for the treatment of bone fracture, osteomalacia, and osteoporosis-like disorders
(Weng et al., 2015).
Plants belonging to the palm family (Arecaceae) are mostly used as a good source of oil in
Asian countries. The most abundant species of this family , that is, Elaeis guineensis is rich in
vitamin E and possess antioxidant and anti-inflammatory properties. V itamin E (tocopherol)
is used as an antiosteoporotic agent and helps in changing the BMD, and remodeling of bone
markers in a high-fat diet-induced metabolic syndrome animal model (Mao et al., 2021).
465
Chine herbs, Salvia miltiorrhiza (SME), secret group of compounds called tanshiones
(tanshinone I, tanshinone IIA, 16-dihydrotanshinone I, crypto tanshinone), and phenolics
(salvianolic acid A, protocatechuic aldehyde, and salvianolic acid B) helps in reduction of
BMD and TRAP activity, responsible for reduced oxidative stress include malondialdehyde
and nitric oxide production in rodents (Liu et al., 2017). It has been reported that these
reduced tumor necrosis factor receptor-associated factor (TRAF) helps in positive
osteoclast formation in in vitro model via c-fos and NFATc1 expression by RANKL
pathway (Figure 18.6) (Lee et al., 2020).
FIGURE 18.6 Ethanol-extracted SME affecting the aberrant level of RANKL, with an expression of TRAF6
and NFATc1 which stop osteoclast differentiation and result in bone resorption (Lee et al., 2020).
⏎
It also suppresses adipogenesis in bone marrow stromal cells along with glucocorticoidinduced cancellous bone loss located in the medullary cavity of bone, which simultaneously
upregulate osteoblastic activity with high expression of Dickkopf-1, RUNX2, peroxisome
proliferator-activated receptor-gamma, and β-catenin in mesenchymal stem cells (MSCs)
(Soelaiman et al., 2012).
E. longifolia found in Malaysia commonly called Tongkat Ali contains high-molecularweight glycoprotein, polysaccharide, and mucopolysaccharides. These molecules increase
testosterone levels in blood, which suppress RANKL and a number of colonies forming
macrophages with osteoclast activity. This mechanism halted bone degradation and maintain bone density as well (Chin and Nirwana, 2015; Shuid et al., 2011).
L. pumila being active in the production of estrogen therefore helps in osteoclast apoptosis
and increase bone formation (Mohd Effendy, 2015). Mainly, the enhanced estrogen which
466
inhibits the secretion of proinflammatory cytokines (IL-1, IL-6) results in osteoclastogenesis (Mohd Effendy and Shuid, 2014).
18.1.4 TREATMENT BY DIFFERENT PIGMENTS
ACN are water-soluble flavonoids found abundantly in various vegetables and fruits. ACN
contain various groups of pigments such as glucosides and galactosidase of cyanidin,
peonidin, delphinidin, petunidin, pelargonidin, and malvidin, which are responsible for
the final color of the berries (Millar et al., 2017). Here are the functions of different
pigments of ACN group as mentioned in Table 18.2 related to the treatment of osteoporosis (Mohamad et al., 2018).
TABLE 18.2 Major ACN that Help in Bone Formation and Could Be Useful for the T reatment of Osteoporosis
Name of the Pigment Source Function Reference
Delphinidin Berries and red wine Antioxidant; Anti-inflammatory Moriwaki
Petunidin Purple potato and
black goji
Malvidin Blueberries Apoptosis-inducing; Antioxidant;
Cyanidin Cherries Antioxidant; Antiangiogenic; Antiviral Hu et al. (2021)
Peonidin Berries Antioxidant; Apoptosis inducing Ren et al. (2021)
Pelargonidin Strawberries Antioxidant Hubert et al. (2014)
Antioxidant Nagaoka et al. (2019)
Camuenho et al. (2022)
Antitumorigenesis
et al. (2014)
There are three major pathways involved through which ACN can act as therapeutics for
osteoporosis including the BMP2 pathway, Wingless-type MMTV integration site family-β
catenin pathway, and broblast growth factor (FGF) pathway. In the BMP2 pathway, it
targets Runx2 downstream and promotes osteoblast differentiation by overexpression of
ALP, bone sialoprotein, osteopontin (OPN) genes (Figure 18.7). Simultaneously, delphinidin-3-rutinoside (D3R) and cyanidin-3-glucoside follow FGF pathway.
Stem cells directed by the transcription factors Sox9, Runx2, and Osterix to deviate to
osteoprogenitor cells are regulated by ACNs leading top regulation of the osteogenesis as
denoted by the gene expression of type 1 collagen (Col1), OPN, OC, and ALP (Salhotra
et al., 2020).
⏎
Its chemical formula is 2-(3,4,5-trihydroxyphenyl) chromenylium-3,5,7-triol and is
profoundly seen in berries. It prevents bone loss by suppressing the NF-kB pathway and
helps in nodule formation and mineralization by upregulating the osteogenic markers.
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It also inhibits the osteoclast differentiation observed in RANKL-induced osteoporosis as
well as the OVX mouse model. A derivative of delphinidin called D3R-treated MC3T3-E1
cells become protective from oxidative damage and generate osteoblastic differentiation by
PI3K/AKT pathway (Nagaoka et al., 2019).
FIGURE 18.7 The effect of different pigments in molecular pathways helps in osteoporosis.
⏎
In vitro experimental results reveal the cellular proliferation of bone marrow macro-
phage (BMM) in the presence of (5-bromo-2′-deoxyuridine) BrdU incorporation assay,
where the cells of 3 × 105 cells/cm2 were cultured in medium and incubated with different
concentrations of BrdU for 4 h, and the incorporation of pigments were detected by ELISA,
and after TRAP staining, the osteoclastogenic activity was also checked and followed by
qPCR analyses of Nfatc1 and CtsK mRNA expression. Results showed that (5-bromo-2′deoxyuridine) BrdU of concentration of 37 µg/ml becomes toxic for BMM cells, so they
used 12.3 µl/ml for osteoclastogenesis assay (Słupski et al., 2021).
Cyanidin chloride (CC) and cyanidin-3-glucoside (C3G) are majorly used to regulate bone formation. The CC helps in the inhibition of osteoclast formation as well as
hydroxyapatite resorption by RANKL-induced signaling pathways, whereas in the OVX
mouse model, it activates NF-kB by degradation of IκB-α, simultaneously accelerating
468
the phosphorylation of ERK. It also induces Ca2+ oscillation and activation of T cells
calcineurin-dependent 1 (NFATc1) in the RANKL signaling pathway. However, the high
dose of CC only accelerates this activity (>10 µg/ml), and surprisingly, the low dosage
(<1 µg/ml) of it shows the opposite activity (Cheng et al., 2018).
C3G is involved in bone nodule formation via ERK1/2 pathway. C3G with 5%(w/w)
treatment helps in the improvement of tibia, vertebral, and femoral BMD values, and
reduces the osteoclastic differentiation markers, that is, cathepsin K, osteoclast-associated
receptor, transmembrane 7 superfamily member and ATPase, H+ transporting, lysosomal
38 kda, V0 subunit d2 (Atp6v0d2), and signicantly inhibits the nuclear translocation of
c-Fos and NFATc1(Park et al., 2015). Therefore, the application of C3G can be a good
therapeutics for bone loss.
18.1.5 OTHER HERBAL SOURCES
Some other herbs also found to have medicinal effects in osteoporosis are as follows.
It probably contains estrogen-like compounds that protect bones; therefore, some medical
doctors prescribe this as a supplement for the treatment also. However, there is no scientific
evidence found till today which shows that it can slow down the bone loss. It contains certain
phytoestrogens (i.e., isoflavones: formononetin, biochanin A, genistein, and daidzein) that
probably bind to estrogen receptors and act as weak agonist, antagonist, or partial agonist,
which activate the isoflavones and remove the glucose residue by certain bacterial enzymes;
therefore, it can be said that the bioavailability of phytoestrogens activity is dependent on
bacterial flora of individual, thus it affects the activity of RC toward bone formation. The
study reveals that in the OVX rat model RC secretes both formononetin and biochanin
A, which contributes to the bone formation process by stimulating the differentiation of
osteoblasts (Kaczmarczyk-Sedlak et al., 2013).
The Latin word “equus” means horse and “seta” means bristle together name Equisetum as
the scientific name of it. It contains silica, which helps strengthen the bones. Therefore, some
practitioners recommend horsetail as a treatment for osteoporosis. It is an abundant source
of silica and helps in the absorption of Ca2+ and in the formation of collagen (Badole and
Kotwal, 2014). The presence of alkaloids, phytosterols, tannins, triterpenoids, and phenolics
in it also helps in preventing bone loss. Equisetum arvense have the secondary metabolites
in the form of quercetin, kaempferol, luteolin, apigenin, oleanolic acid, betulinic acid, and
ursolic acid, having the catabolic activity upon osteoblasts which form the connective tissue
by the deposition of Ca2+ and other minerals help in decrease of osteoclast and stimulate the
469
osteoblast activity, and synthesis of collagen, glycosaminoglycan and collagen. However,
still detailed research is still under investigation to decide the treatment for osteoporosis
(Corletto, 1999).
The process of building bone and maintaining bone strength relatively depends upon
the uptake of calcium-rich food including several dairy products such as cheese, yogurt,
milk, and fermented milk products. These contain several building blocks of bone health
including protein, magnesium, phosphorous, and vitamin B
(Muñoz-Garach et al.,
12
2020). Other than these, nut-based milk, orange juice, cereals, tofu, salmon, and fish with
bones, like sardines, and plant-based food including kale, cabbage, and other leafy green
vegetables contain calcium. Simultaneously, vitamin D is needed for the absorption of
Ca2+ mainly derived from sun exposure. Other than that, food sources of vitamin D include
fatty fish (such as trout, salmon, tuna, and mackerel) and fish liver oils, beef liver, egg
yolks, fortified milk, other fortified foods (milk alternatives, breakfast cereals, juice), and
mushrooms (Lips and Schoor, 2011).
18.1.6 NATURAL PLANT-BASED ALKALOIDS
Plant-based natural alkaloids such as polycyclic, nitrogen-containing, and basic compounds
possess medicinal effects for osteoporosis treatment because of their chemical structures.
These are mainly classified into six main categories according to their chemical structures,
that is, isoquinoline alkaloids, quinolizidine alkaloids, piperidine alkaloids, indole alkaloids,
pyrrolizidine alkaloids, and steroidal alkaloids. These are the groups of alkaloids which
influence mesenchymal stem cells differentiation, improve osteoblast proliferation, stimulate
osteoblast autophagy , and suppress osteoclast formation for the osteoporosis treatment, which
follows several important signaling pathways, including TNF-α receptor-associated NF-kB
signaling, activation of p38 MAPK pathway in osteoblasts, and triggering the wingless and
int-1 pathway in mesenchymal stem cells. The details of natural alkaloids are mentioned in
T able 18.3.
18.1.7 ESSENTIAL MARKERS INVOLVED IN BONE FORMATION AND RESORPTION FOR OSTEOPOROSIS TREATMENT
To produce active osteoblast, serum-derived ALP, bone-specific ALP, OC, and byproducts
of collagen neo synthesis (procollagen type I propeptides) are mainly involved. Serumderived ALP is membrane-bound enzyme usually presents in the liver, bone, and placenta
at the outer cellular surface, which plays an important role in the osteoid formation and
mineralization (Harris, 1990). In contrast, the bone-specific ALP derives by several
methods such as electrophoresis, precipitation, heat denaturation, selective inhibition, and
TABLE 18.3 Description of Natural Alkaloids Derived from Plant Sources for Osteoporosis Treatment (Lin et al., 2022)
Alkaloid Source Experimental model (in vitro/in
vivo studies)
Berberine
Tetrahydropalmatine
Boldine
Tetrandrine
Fangchinoline
Sinomenine
Lycorine Amaryllidaceae
Cepharanthine
Nitidine
Piperine Piperaceae family RAW 264.7 macrophages induced
Coptidissp.
Corydalis sp.
Peumus sp.
Stephania tetrandra
S. Moore
Stephania tetrandra
S. Moore
Sinomenium acutum
(Thunb.) Rehder and
E.H. Wilson
family
Stephania abyssinica
(Quart.-Dill. and A.
Rich.) W alp
Zanthoxylum nitidum
(Roxb.) DC
OVX and glucocorticoid-induced
mouse models in in vivo and MSCs,
MC3T3-E1cells with influence of
BMMs induced by RANKL
OVX-induced models; BMMs
induced by RANKL
OVX-induced models 20 mg/kg for mouse model
OVX, and titanium particle-induced
mouse models and BMMs induced
by RANKL
OVX and prednisolone-induced
mouse models and BMMs induced
by RANKL
Mycobacterium tuberculosis
H37Ra-induced mouse model
and MC3T3-E1 cells with BMMs
induced by RANKL
OVX and wear particle-induced
mouse model and BMMs induced
by RANKL
OVX-induced mouse models and
BMMs induced by RANKL
DO
by RANKL and breast cancer cells
Dose Mechanism of action Reference
20–100 mg/kg for mouse
model and 0.05–30 μM for
in vitro
4 mg/kg for mouse model
and 4.75–19.00 μM for in
vitro
and 25–75 μM for in vitro
30–60 mg/kg for mouse
model and 0.25–1 μM for
in vitro
5–10 mg/kg in mouse
model and 0.25–1 μM in
vitro
80–150 mg/kg in mouse
model and 0.1–1 μM in
vitro
2.5 mg/kg in in vivo and
0.1–0.4 μM in vitro
20 mg/kg in in vivo and
0.0625–1 μM in vitro
6 mg/kg in in vivo and
0.125–1 μM in in vitro
5–100 μM in vitro
Malondialdehyde↓, Superoxide
dismutase↑
TNF-α↓, IL-6↓, CTX-1↓,
TRACP5b↓
CTX-1↓ Chen et al. (2018)
IL-1α↓,IL-1β↓, IL-6↓, TNF-α↓,
CTX-1↓, TRAP5b↓, [Ca2+] ↓
Caspase-3↓, B-cell lymphoma-2↑,
microtubule-associated protein 1
light chain 3↑, autophagy-related
gene-5↑, Beclin-1↑
TRACP5b↓, RANKL↓, OPG↑,
OC↑, ALP↑, collagen type I alpha
1↑, OPN↑, [Ca2+]↓
p-P38↓ Chen et al. (2015)
NFATc1↓ Zhou et al. (2018)
NFATc1↓ Liu
ALP↑ Deepak
⏎
Adil
et al. (2017);
Chen et al. (2021)
Zhi et al. (202)
Liu et al. (2020)
Zhu et al. (2019)
He et al. (2016)
et al. (2016)
et al.
(2015)
470
TABLE 18.3 (Continued)
Alkaloid Source Experimental model (in vitro/in
vivo studies)
Arecoline
Matrine
Oxymatrine
Cytisine Leguminosae family OVX-induced mouse models and
Harmine
Vindoline
Rutaecarpine
Areca catechu L.
Sophora flavescens
Aiton
Sophora flavescens
Aiton
Peganum harmala L.
Catharanthus roseus
(L.) G. Don
Acronychia
acronychioides (F.
Muell.) T. G. Hartley
LPS-induced mouse models and
MC3T3-E1 cells; BMMs induced
by M-CSF or RANKL
OVX-induced mouse models and
BMMs induced by RANKL
OVX-induced mouse models and
BMMs induced by RANKL
BMMs induced by RANKL
OVX-induced mouse models
and RAW 264.7 cells induced by
RANKL
OVX-induced mouse models and
BMMs induced by RANKL
OVX-induced mouse models
and RAW 264.7 cells induced by
RANKL
Dose Mechanism of action Reference
10 mg/kg in vivo and
25–100 μM in vitro
50 mg/kg in vivo and
1–-4 μM in vitro
10 mg/kg in vivo and
100–400 μM in vitro
25 mg/kg in vivo and
12.5–25 μM in vitro
10 mg/kg in vivo and
0.3–3 μM in vitro
10 mg/kg in vivo and
2.5–10 μM in vitro
5 mg/kg in vivo and
1–10 μM in vitro
ALP↑ Liu et al. (2020)
IL-6↓, TNF-α↓, TRACP5b↓ Chen et al. (2017)
CTX-1↓ Jiang et al. (2021)
NFATc1↓ Qian et al. (2020)
Platelet-derived growth
factor-BB↑, Type H vessel↑
Reactive oxygen↓ Zhan et al. (2020)
OPG↑, ALP↑, CTX-1↓ Tian et al. (2019)
Huang et al.
(2018)
471
472
immunoassays from plant sources, having an important role in osteoblast production too
(Hill and Wolfert, 1990). OC is abundantly found in bone matrix mainly as anon–collagen
protein. It is released by osteoblast in the extracellular matrix into the blood circulation
during bone anabolic activities, and therefore considered as an important marker of
the production of osteoblastic activity (Brown, 1984). Procollagen type I propeptide is
a profuse form of collagen present in bone. The amino (N-)terminal propeptide (PINP)
and the carboxy (C-)terminal propeptide (PICP) are attached to precursor molecules of
collagen-I (procollagen type I) which are enzymatically cleaved by specific proteases
during the formation of collagen-I in bone matrix. As the production of both PINP and
PICP is associated with collagen-I synthesis, their detection as markers is important for
osteoblast production and bone formation (Bauer et al., 2012).
The bone resorption-related markers are a product of collagen, that is, hydroxyproline
or the various collagen cross-links and telopeptides. Other than these, receptor activators
such as RANKL, OPG, TRAP, and cathepsin K release during bone resorption. TRAP
serves as a nonspecic marker of bone-resorption activity. RANKL produced by osteoblasts
binds to the RANK on the surface of osteoclast precursor cells, resulting in the activation
of MAPKs, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), and
NF ATc1 signaling pathway . Therefore, RANKL is involved in the osteoclast dif ferentiation
(Khosla, 2001). The protease enzyme cathepsin K found in osteoclasts is a striking target
for osteoclastic activity. It releases impaired matrix digestion enzymes in postmenopausal
women with osteoporosis.
The recent clinical approaches for osteoporosis by using natural supplements create
an emphasis upon these molecular markers mentioned and summarized. The study of the
natural alkaloids and supplements has been carried out along with a detailed mechanism
of action based upon these marker-specic signaling pathways and it is still continuing for
the development of therapeutic applications for osteoporosis. However, detailed research
on traditional and natural medicine is needed to explore more to achieve the uniformity
in the treatment of osteoporosis. The clinical practice using natural supplements has been
chosen as the better treatment approach for future because of lesser side effects, ecofriendly production, lesser production cost, and higher intensity of improvement of patient
condition. As modern pharmaceuticals aim at quick and specic responses, most of the
biomolecules and established therapies for osteoporosis have several side effects causing
high risk to the patient. Therefore, herbal supplement applications for the treatment of
osteoporosis will give a better prospect of treatment which can be the best possible way to
treat the disease in the near future.
18.2 CONCLUSION
In a scenario of treatment lines for osteoporosis, nowadays increase in medical visits,
hospitalizations, and nursing home medication give a huge financial burden to our
economy, therefore screening of these diseases and treatment aspects could be applied by
the implementation of natural product-based therapies to the mass population worldwide.
These natural product-based supplemental products will give the most cost-effective