Research Progress On The Mechanisms Of Action Of Cistanche Deserticola Ma Extracts in The Prevention Of Osteoporosis Ⅱ
Mar 14, 2025
2. Classical Signaling Pathways Involved in Bone Metabolism in Osteoporosis
Osteoporosis is primarily characterized by bone loss and the deterioration of bone microarchitecture. Osteoclasts, the primary cells responsible for degrading bone matrix, play a crucial role in the gradual progression of osteoporosis when their function becomes abnormal. Bone tissue maintains its mechanical strength and self-repair capability through a continuous remodeling process, in which osteoclasts resorb old bone, followed by osteoblasts forming new bone to replace it. Bone resorption typically lasts about 4–6 weeks, while bone formation requires approximately 4–6 months. Under healthy conditions, the balance between bone resorption and formation is tightly regulated and critical for maintaining normal bone density and mineral homeostasis [49-50]. However, in osteoporosis, this balance is disrupted, resulting in weakened osteoblast function and enhanced osteoclast activity. Consequently, bone formation cannot keep up with the pace of bone resorption, leading to reduced bone mass and increased skeletal fragility [51]. The development of osteoporosis is closely related to bone metabolism imbalance and involves multiple classical signaling pathways, including the osteoprotegerin (OPG)/receptor activator of nuclear factor kappa-B (RANK)/RANK ligand (RANKL), Wnt/β-catenin, bone morphogenetic protein-small mothers against decapentaplegic (BMP-Smad), Hedgehog, Notch, and chemokine signaling pathways.
Herbal Cistanche Supplements to Promote Bone Resorption
2.1 OPG/RANK/RANKL Signaling Pathway
The OPG/RANK/RANKL signaling pathway is one of the most extensively studied pathways in bone homeostasis and effectively promotes the differentiation and activity of osteoclasts [52-53]. After being secreted by osteocytes, RANKL binds to its specific receptor, RANK, on osteoclasts, enhancing their differentiation and activation [54]. OPG, a decoy receptor mainly produced by osteoblasts, competes with RANK to negatively regulate osteoclast differentiation [55]. Upon binding, RANKL and RANK form a trimer that recruits tumor necrosis factor receptor-associated factor 6 (TRAF-6). TRAF-6 regulates osteoclast maturation, differentiation, or apoptosis by activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) via inhibitor-κB kinases and NF-κB-inducing kinase [56]. TRAF-6 can also activate cellular Src (c-Src), which stimulates phosphatidylinositol 3-kinase (PI3K). PI3K activates protein kinase B (AKT serine/threonine kinase), which subsequently regulates osteoclast differentiation [57].
Moreover, the RANKL/RANK interaction activates the mitogen-activated protein kinase (MAPK) signaling pathway through extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), or P38MAPK [58-59]. The MAPK pathway activates transcription factors such as c-Fos, activator protein 1 (AP-1), and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), which in turn regulate the expression of matrix metalloproteinases (MMPs) to stimulate osteoclast precursor differentiation into osteoclasts [60]. Recent studies have shown that protein phosphatase 2A promotes RANKL expression [61]. Additionally, the leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) has been identified as another receptor for RANKL, competitively binding to RANKL and inhibiting the classical RANKL/RANK signaling pathway during osteoclast differentiation [62].
2.2 Wnt/β-Catenin Signaling Pathway
The Wnt signaling pathway includes both canonical and non-canonical pathways, among which the canonical Wnt signaling pathway has been shown to play a particularly important role in bone remodeling by osteoblasts [63]. In osteoblasts, Wnt proteins bind to low-density lipoprotein receptor-related protein 5/6 (LRP5/6) and frizzled receptors on the osteoblast membrane, promoting the stabilization of intracellular β-catenin [64]. β-Catenin can then translocate to the nucleus, where it regulates the expression of Runt-related transcription factor 2 (Runx2), a key osteoblast-specific transcription factor, thereby influencing osteoblast activity [65]. Furthermore, the Wnt/β-catenin signaling pathway promotes the differentiation of mesenchymal stem cells (MSCs) into osteoblasts and prevents their differentiation into adipocytes or osteoclasts [66]. The accumulation of β-catenin also facilitates the osteogenic differentiation of MSCs [67]. As such, the Wnt/β-catenin signaling pathway may serve as a critical therapeutic target for osteoporosis.
2.3 BMP-Smad Signaling Pathway
Bone morphogenetic proteins (BMPs) are important members of the transforming growth factor-beta (TGF-β) superfamily, with BMP2, 4, 7, and 9 playing crucial roles in osteoblast differentiation [68]. BMPs bind to specific receptors on the cell membrane, leading to the phosphorylation of downstream Smad proteins, which subsequently activate transcription factors such as Runx2 and osterix. The TGF-β signaling pathway enhances BMP-induced bone formation by increasing BMP expression. Bone resorption induces osteoblast recruitment under the influence of a TGF-β1 concentration gradient [69]. The BMP-2 signaling pathway primarily promotes the proliferation of MSCs and their specialized differentiation into osteoblasts, thereby ensuring bone tissue repair [70].
2.4 Hedgehog Signaling Pathway
The Hedgehog signaling pathway is composed of Hedgehog ligands (IHH, Shh, DHH), receptors (Patched, SMO (Smoothened)), and intracellular signaling molecules (e.g., Gli oncogenes) [71]. The Hedgehog pathway promotes the differentiation of MSCs into osteoblasts and prevents their differentiation into adipocytes by upregulating Runx2 expression, thereby mitigating age-related decreases in osteoblast numbers and bone loss [72]. This pathway also enhances the expression of osterix (Osx), a transcription factor essential for osteoblast maturation [73].
2.5 Notch Signaling Pathway
The role of the Notch signaling pathway in bone metabolism remains controversial. Studies have shown that Jagged and Delta-like Notch ligands can bind to Notch receptors and promote the translocation of the Notch intracellular domain to the nucleus, thereby facilitating osteoblast differentiation in vitro [74]. However, some research indicates that Notch homolog 1 (NOTCH1) inhibits osteoclastogenesis, while NOTCH2 enhances osteoclast differentiation [75]. Therefore, the role of the Notch signaling pathway in bone remodeling requires further clarification.
2.6 MAPK Signaling Pathway
The mitogen-activated protein kinase (MAPK) signaling pathway is highly conserved throughout biological evolution and is widely involved in various physiological and pathological processes [76]. In eukaryotic cells, multiple MAPK pathways exist to regulate life activities such as gene expression, programmed cell death, and cell differentiation [77]. Among these, P38, ERK1/2, and JNKs are the most extensively studied MAPK pathways. They transmit signals downstream to RANKL, which binds to the RANK receptor to activate transcription factor AP-1, further propagating the signaling pathway [78].
2.7 Interrelations Among Bone Metabolism-Related Signaling Pathways
These signaling pathways collaboratively regulate the balance between bone formation and resorption. Their interrelations are illustrated in Figure 1, and their dysregulation is a key mechanism underlying osteoporosis. Drug development and regulatory strategies targeting these pathways are becoming important directions for osteoporosis treatment.
3. Mechanisms of Cistanche deserticola in Anti-Osteoporosis Effects
Studies have shown that Cistanche deserticola extract (CDE) has therapeutic effects on osteoporosis, primarily by influencing the activities of osteoblasts and osteoclasts, thereby alleviating osteoporosis symptoms [79]. Cistanche deserticola and its active components demonstrate potential for the prevention and treatment of osteoporosis through various mechanisms, including mimicking estrogen to slow postmenopausal bone loss, promoting osteoblast activity and enhancing mineral deposition, providing antioxidant protection to reduce oxidative stress damage to bone cells, and regulating key signaling pathways involved in bone metabolism, such as NF-κB, PI3K/AKT, Wnt/β-catenin, and MAPK [80-82]. These combined effects not only inhibit the formation and activity of osteoclasts but also promote new bone formation, improving bone microarchitecture and strength. The mechanisms are summarized in Table 3. Therefore, CDE is considered a promising natural compound for anti-osteoporosis therapy.
However, current research on CDE's anti-osteoporosis effects lacks sufficient clinical trial data due to several challenges. First, research on Cistanche deserticola has traditionally focused on its kidney-tonifying and yang-strengthening properties in traditional Chinese medicine, with modern medical research on its role in osteoporosis starting relatively late, leaving foundational studies underdeveloped. Second, the high cost of clinical trials, combined with relatively low returns from the herbal medicine market, limits financial support for research. Additionally, clinical trials for traditional Chinese medicine must adhere to modern medical standards, but the complexity of herbal formulations, coupled with incomplete regulations and standards, presents significant barriers. The lack of international collaboration further constrains research resources and technical support.
Moreover, the absorption, distribution, metabolism, and excretion (ADME) processes of CDE are not yet fully understood. Existing studies suggest that its phenylethanoid glycosides and polysaccharides are primarily absorbed through the intestine, distributed to organs such as the liver, kidneys, and bones, metabolized in the liver and intestine, and eventually excreted through urine and feces [83-85]. Future research is needed to further elucidate the ADME process and its relationship to pharmacological effects.
