Research Progress On Mechanism Of Effective Components Of Tonifying Kidney Yang Chinese Medicine in Treating Osteoporosis

Keywords: Active ingredient; Osteoporosis; Signaling pathway;Review

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Osteoporosis (OP) is a systemic metabolic skeletal disorder typified by a deterioration in bone mass, bone quality and microarchitecture throughout the body and an imbalance in bone remodelling caused by more osteoclast-mediated bone resorption than osteoblast-mediated bone formation, which in turn leads to this pathological skeletal disease [1]. Osteoporosis is prevalent in the aging population and is highly susceptible to the risk of osteoporotic fractures, which can lead to serious complications and a high mortality rate [2]. According to epidemiological surveys, China has entered a severely aging society with 15.5% of the population aged 60 years or older and approximately 10.1% of the population aged 65 years or older, and the prevalence of OP in people aged 60 years or older is 36%, with significantly more women than men [3].

In Chinese medicine, osteoporosis belongs to the category of "bone impotence" and "bone paralysis", and according to the theory of Chinese medicine, "the kidney is the master of bone production and marrow". In recent years, Chinese medicine has achieved remarkable results in the treatment of OP, as it can be tailored to the patient's condition, effectively grasp the rules of medication and has fewer side effects. In this paper, we present the current status of the active ingredients of single herbal medicine for tonic kidney yang to prevent and treat OP, so as to provide reference for future scholars and hopefully contribute to the development of new drugs and clinical trials.

1. Mechanism of action of the active ingredients of Chinese herbal medicine in the treatment of kidney yang deficiency OP

1.1 Epimedium

Epimedium, also known as Xianling Spleen, is an important medicine for tonifying the kidney and strengthening yang. The herb is pungent, sweet and warm. It belongs to the liver and kidney meridians. It has the ability to tonify the kidney

It has the effect of tonifying the kidneys, strengthening the muscles and bones, and dispelling wind and dampness. Contains Epimedium, Epimedium hypoglycoside, Epimedium elements, Epimedium total flavonoids and other components.

1.1.1 Icariin (ICA)

Icariin is an active ingredient isolated from Epimedium, which has immunomodulatory, anti-inflammatory and anti-osteoporosis effects.

Icariin is an active ingredient isolated from Icari. In a study of Icariin in rat BMSCs, it was found that Icariin promoted the expression of Wnt/β-catenin signaling pathway key factors and osteogenesis-related factors, and increased the expression levels of β-catenin, ρ-GSK-3β, Runx2 and c-myc, demonstrating that Icariin promoted the osteogenic differentiation of rat BMSCs by activating the Wnt/β-catenin signaling pathway. It was shown that Epimedium promotes osteogenic differentiation of BMSCs through activating Wnt/β-catenin signaling pathway to treat OP fractures[4]. Another research team [5] investigated the mechanism of edgehog signaling pathway mediated by Icariin to promote osteogenic differentiation of MC3T3-E1 cells. The experiments showed that Icariside could activate the Hedgehog signalling pathway by upregulating the expression level of Shh protein and ALP activity, and promote the osteogenic differentiation of MC3T3-E1 cells. It was shown that Epimedium could promote osteogenic differentiation of MC3T3-E1 cells, promote bone formation, increase bone mineral density and prevent OP by upregulating Shh protein expression and ALP activity.

Sun et al[6] found that ICA could promote osteogenic differentiation of MC3T3-E1 cells, promote bone formation, increase bone mineral density and prevent OP through estrogen. In their study on the mechanism of action of ICA on hFOB1.19 osteoblasts, they found that ICA could upregulate the expression levels of OPG and RANKL and the OPG/RANKL ratio through the action of estrogen in hFOB1.19 osteoblasts, thereby stimulating cell proliferation and regulating bone mineral density. This in turn stimulates cell proliferation and regulates bone formation.

1.1.2 Icariside

Icariside is a flavonol glycoside, which is one of the main components of Icaris, mainly formed by removing the glycosyl group of Icariside

Icariside is a flavonol glycoside formed by the removal of the glycosyl group of Icaris glycosides, mainly containing Icariside I (ICA I) and Icariside II (ICA II). It has been shown to have anti-osteoporosis, anti-hypoxia and anti-cancer activities. A research team[7] used Icariside II to intervene in BMSCs of Beagle dogs The results showed that ICA II increased ALP activity and calcium deposition, and significantly enhanced osteogenic differentiation of BMSCs. The results showed that ICA II increased ALP activity and calcium deposition and significantly enhanced osteogenic differentiation in BMSCs. A research team[8] also studied the effects of ICA II on osteogenic differentiation of rat osteoblasts by culturing SD rat osteoblasts in vitro. The results showed that under the intervention of ICA II, it could increase ALP activity through activating the p38MAPK The results showed that under the intervention of ICA II, ALP activity and OPG and p38MAPK expression could be increased through activation of the p38MAPK signaling pathway, thus promoting osteoblast formation. Another related experiment [9] investigated the effects of Icariin I and Icariin II on the differentiation of RAW264.7 cells and found that both could inhibit the expression of OPG and p38MAPK through In a study by [9] on the effect of Icariin I and Icariin II on the differentiation of RAW264.7 cells, it was found that both could slow down the rate of bone resorption by inhibiting the expression of genes in the AP-1/NFATc1 signalling pathway, thus achieving osteoprotective effects.

1.1.3 Icaritin (ICT)

Icaritin is a flavonoid that is one of the main metabolites of Icariside and can also be produced by the in vivo metabolism of Icaris hypoglycoside.

It is also produced by the in vivo metabolic deglycosylation of Icaritin. In a study conducted by a research team [10], we found that epimedium could promote the expression of BMP-2 and BMP-9, and significantly up-regulate the expression of osteogenic factors such as Runx2 and Qsterix, demonstrating that it could promote osteogenesis in rat BMSCs through the activation of the BMP/Runx2/Osx signalling pathway. It was demonstrated that it could promote osteogenic differentiation and bone formation in rat BMSCs through the activation of BMP/Runx2/Osx signaling pathway. By interfering with human osteoblasts, epimedium can dose-dependently increase the expression level of p-STAT3, thereby upregulating CXCR4 protein expression and promoting osteoblast proliferation[11].

1.1.4 Total flavonoids of epimedium (TFE)

Total flavonoids of Epimedium can increase the mRNA and protein expression levels of BMP, Runx2 and Osx in bone tissue of PMOP rats, activate the BMP/Runx2/Osx signalling pathway, promote bone formation and enhance bone resorption compared to bone resorption, thus exerting a beneficial effect on improving OP[12] . The research team of Liang Guangsheng et al[13] found that total flavonoids from Epimedium could promote ALP activity and protein expression levels of osteogenic transcription factors BMP-2, RunX2 and OSX through activating the BMP-2/RunX/OSX signaling pathway, thus promoting the directional osteogenic differentiation of rat BMSCs, i.e. the level of osteogenic differentiation of BMSCs was increased. In addition, some scholars[14] used SAMP6 mouse osteoblasts as a research object, and used total flavonoids of Epimedium to  study found that TFE could activate the Wnt/β-catenin signaling pathway and increase the mRNA and protein expression of β-catenin, Runx2, cyclin. The study found that TFE could promote the proliferation of mouse osteoblasts and prevent OP by activating the Wnt/β-catenin signaling pathway and increasing the mRNA and protein expression of β-catenin, Runx2 and cyclin D1.

1.2 Baji Tian

Ba Ji Tian, pungent, sweet and slightly warm. It belongs to the liver and kidney meridians. It has the effect of tonifying kidney yang, strengthening tendons and bones and dispelling wind and dampness. Contains

It contains Ba Ji Tian polysaccharide, Ba Ji Tian oligosaccharide, methyl isocyanin-1-methyl ether and other active ingredients.

1.2.1 Morinda officinalis polysaccharide (MOP)

Morinda officinalis polysaccharide is one of the active ingredients of Morinda officinalis, which accounts for roughly 20% of Morinda officinalis herbs, with various pharmacological effects such as anti-osteoporosis, anti-depression, immune enhancement and anti-aging. A research team [16] studied the effect of MOP on the osteogenic-lipogenic differentiation of rBMSCs, and the results showed that after MOP treatment, the phosphorylation of PI3K and AKT was increased and the PI3K/AKT signaling pathway was activated, thus promoting the osteogenic differentiation of rBMSCs and partially reducing OP in OVX rats. A research team[16] used Bacopa monniera polysaccharide to intervene in OVX rats and observed that the OPG content increased, RANKL decreased and RANKL/OPG decreased in ovariectomized rats, thus achieving the purpose of inhibiting osteoclast proliferation, inhibiting bone resorption and preventing PMOP.

1.2.2 Morinda Oligosaccharide (MO)

Morinda oligosaccharide is the main medicinal component of Morinda oligosaccharide, which has antidepressant, anti-aging, anti-osteoporosis, anti-inflammatory and anti-dementia and other effects. Some experiments found that [17], using Baji Tian oligosaccharide intervention OVX rats, Baji Tian oligosaccharide can be used to improve bone trabecular morphology and bone microstructure by upregulating OPG activity in rat femur, reducing RANKL expression, and then inhibiting osteoclast differentiation and slowing down the rate of bone loss.

1.2.3 Rubiadin-1-methyl ether (RBM)

Rubiadin-1-methyl ether is a naturally occurring anthraquinone compound isolated from the roots of Bacopa monniera. In the application of

The results showed that RBM attenuated the degradation of IκBα and phosphorylation of NF-κB p65, and decreased the nuclear translocation of p65, i.e. RBM inhibited the activation of NF-κB [18]. NF-κB signalling pathway is an important signalling pathway that inhibits bone resorption, so RBM inhibits the activation of NF-κB signalling pathway, thereby inhibiting osteoclast resorption and thus maintaining bone RBM inhibits the activation of the NF-κB signaling pathway, thereby inhibiting osteoclast resorption and maintaining bone homeostasis [18].

1.3 Cistanche

Herba Cistanches, sweet, salty and warm in nature. It belongs to the kidney and large intestine meridians. It is effective in tonifying the kidney and Yang, benefiting the essence and blood, and moistening the bowels and opening the bowels.Cistanches Tubulosa contains total glycosides, polysaccharides, ergosterol and 6-acetyl ergosterol.

1.3.1 Total glycosides of cistanche  and cistanche polysaccharide (CCS) 

Total glycosides of Cistanche and Cistanche polysaccharide (CDP) are derived from the Chinese herbal medicine Cistanche cistannii, with anti-inflammatory, anti-tumour, anti-osteoporosis, and anti-oxidant activities.

They have anti-inflammatory, anti-tumor, anti-osteoporosis, and anti-oxidant activities. It has been reported[19] that Cistanche cistanche total glycosides and polysaccharides were used to intervene in SAMP6 mice to observe the effects of GCS and CDP on Wnt/β-catenin.

The results showed that GCS and CDP could upregulate the effects of BMP-2, OCN, OPG, p-GSK-3β, and p-GSK-3β on the Wnt/β-catenin signalling pathway.

The results showed that GCS and CDP could activate the Wnt/β-catenin signaling pathway by upregulating the expression of BMP-2, OCN, OPG, p-GSK-3β and decreasing the expression of RANKL and p-β-catenin, thus

This activates the Wnt/β-catenin signalling pathway, promotes osteogenesis in SAMP6 mice, slows down bone loss, improves bone microstructure damage and thus prevents OP.

1.3.2 Ergocalciferol (acteoside)

Ergasteride is obtained from Cistanche Tubulosa and is one of the active ingredients in the phenylethanoid glycosides group of active ingredients of Cistanche tubulosa.

It has immune-enhancing, antioxidant and anti-inflammatory effects. A team of researchers[20] studied the effects of acteoside on bone metabolism in OVX rats.

In a study on the effects of acteoside on bone metabolism in OVX rats, the team[20] found that acteoside decreased the expression levels of TRAF6, RANKL, NF-κB and NFAT2, as well as the expression levels of PI3K, AKT and c-alpha-actin.

Therefore, acteoside can inhibit bone resorption by inhibiting the RANKL/TRAF6/NF-κB signaling pathway and can inhibit bone resorption by increasing the expression levels of PI3K, AKT and c-Fos and can promote bone formation by activating PI3K/AKT signaling pathway, making the rate of bone formation greater than the rate of bone loss This can improve bone metabolism and prevent OP.

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