Osteoporosis involves osteoblast/clast imbalance and impaired autophagy. The review links dysregulated autophagy to bone loss and highlights TCM multi-target benefits via PI3K/AKT/mTOR, AMPK/mTOR, PINK1/Parkin pathways.
Review Article
Osteoporosis involves osteoblast/clast imbalance and impaired autophagy. The review links dysregulated autophagy to bone loss and highlights TCM multi-target benefits via PI3K/AKT/mTOR, AMPK/mTOR, PINK1/Parkin pathways.
Osteoporosis, a common and high-incidence bone disease, is characterized by low bone density and degradation of bone microstructure. Its pathogenesis is intricate, with the imbalance of osteoblast and osteoclast functions being a core element and abnormal autophagy also serving as a key pathogenic factor. This paper delves into the intrinsic link between the pathological mechanisms of osteoporosis and autophagy. It comprehensively outlines the manifestations of bone metabolic imbalance, interprets the normal physiological role of autophagy in bone metabolism, and explores the abnormal changes and mechanisms of autophagy in osteoporosis. Furthermore, the paper focuses on the cutting-edge research progress in treating osteoporosis with traditional Chinese medicine (TCM) by targeting autophagy-related pathways, including the PI3K/AKT/mTOR, AMPK/mTOR, and PINK1/Parkin signaling pathways. It highlights the unique advantages of TCM in multi-target and multi-pathway intervention, clarifies future research directions, and aims to establish a more comprehensive and systematic strategy for preventing and treating osteoporosis with TCM.
Osteoporosis (OP) has emerged as a pervasive global health crisis, currently affecting over 200 million individuals worldwide. Characterized by systemic impairment of bone mass and micro-architectural deterioration, this "silent epidemic" dramatically increases skeletal fragility, leading to susceptibility to fractures that impose a staggering burden on healthcare systems and significantly diminish patient quality of life1,2. As the global population ages, the incidence of OP-related fractures is projected to rise exponentially, necessitating a deeper understanding of its molecular underpinnings and the development of more sophisticated therapeutic interventions.
Physiologically, skeletal integrity relies on the rigorous maintenance of bone homeostasis, a dynamic equilibrium between bone formation by osteoblasts and bone resorption by osteoclasts. Unlike monogenic disorders, OP arises from a convergent disruption of this osteoblast-osteoclast coupling. Within this complex regulatory network, autophagy acts as a central "rheostat" or cellular quality control mechanism. This evolutionarily conserved catabolic circuit is essential for recycling damaged organelles and proteins to sustain osteocyte viability and function. However, this delicate balance is easily perturbed; an age-dependent decline in autophagic flux can amplify oxidative stress and trigger inflammatory cascades, thereby tipping the metabolic scale toward net bone loss3,4,5,6. Consequently, dysregulated autophagy is not merely a bystander but a critical driver in the pathogenesis of bone metabolic disorders.
Current pharmacological landscapes for OP are dominated by Western medicine, utilizing agents such as bisphosphonates and biological inhibitors. While these interventions effectively target specific nodes in bone remodeling, they are often associated with limitations, including plateauing efficacy and a "single-target" approach that may fail to address the systemic complexity of the disease2. This therapeutic gap highlights an urgent need for strategies that can modulate the intricate signaling networks governing bone metabolism holistically. In this context, Traditional Chinese Medicine (TCM) offers a compelling alternative paradigm. Distinct from the reductionist approach of synthetic drugs, TCM formulations possess a multi-component, multi-target pleiotropy that positions them as rational, systems-level interventions for next-generation OP therapeutics. Emerging evidence suggests that TCM formulations modulate multiple autophagic hubs-most notably the PI3K/AKT/mTOR, AMPK/mTOR, and PINK1/Parkin signaling pathways-simultaneously restoring osteoblast differentiation while restraining osteoclast hyperactivity7.
This review aims to synthesize the cutting-edge research linking the pathological mechanisms of OP to autophagy dysfunction. We comprehensively examine the manifestations of bone metabolic imbalance and explore how specific TCM interventions target autophagy-related signaling pathways. By elucidating these molecular mechanisms, we aim to clarify future research directions and establish a theoretical foundation for a more comprehensive, systematic strategy for preventing and treating osteoporosis with TCM.
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The relationship between the pathogenesis of osteoporosis and autophagy
The manifestation of bone metabolism imbalance in osteoporosis: Osteoporosis (OP) can be divided into two major types based on its etiological characteristics: primary and secondary. Primary OP is associated with a variety of factors, including aging, genetic background, and environmental influences, while secondary OP has more definitive causes, mainly resulting from specific diseases or the use of certain medications7. Currently, it is widely accepted in the field of modern medicine that the regulation mechanism of bone metabolism imbalance is the key factor in inducing OP, which essentially involves the disruption of the dynamic balance of bone metabolism, leading to a series of pathological changes8. From the perspective of bone metabolism, the balance between bone formation and bone resorption is crucial for maintaining skeletal health. In patients with OP, this balance is disrupted, with bone resorption exceeding bone formation, resulting in a gradual decrease in bone mass and destruction of bone microstructure9. Under normal physiological conditions, the levels of bone formation markers and bone resorption markers are relatively stable, maintaining a dynamic equilibrium. However, in OP, the levels of bone formation markers such as bone alkaline phosphatase (BALP) and type I procollagen N-terminal propeptide (PINP) decrease, while the levels of bone resorption markers such as tartrate-resistant acid phosphatase 5b (Tracp-5b) and type I collagen C-terminal peptide (CTX-1) increase. These changes directly lead to bone loss and structural damage10. At the cellular level, regulatory T cells (Treg) and T helper 17 cells (Th17) play a central role in the regulation of bone metabolism. Compared with healthy individuals, patients with OP have a lower proportion of Treg cells and a higher proportion of Th17 cells, disrupting the Treg/Th17 balance. Specifically, the levels of cytokines secreted by Treg cells, such as interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β), decrease, while the levels of cytokines secreted by Th17 cells, such as interleukin-17 (IL-17) and tumor necrosis factor-α (TNF-α), increase. These changes in cytokine levels affect the OPG/RANKL/RANK signaling axis, promoting osteoclast differentiation and inhibiting osteoblast secretion of OPG, thereby exacerbating the severity of osteoporosis11,12.
The normal physiological role of autophagy in bone metabolism
Maintenance of bone cell homeostasis and function
Autophagy plays a fundamental role in the physiological processes of bone cells and is crucial for maintaining their homeostasis. During bone formation, the precursors of osteoblasts experience a decrease in autophagic activity for approximately 12 h, indicating the significant role of autophagy in the early stages of osteoblasts. The autophagosomes accumulated in undifferentiated mesenchymal stem cells can be rapidly degraded to provide energy and metabolic precursors for cell differentiation. Moreover, autophagy can protect osteoblasts from the toxic effects of lead chloride and other harmful stimuli, thereby maintaining their normal function1,7.
Regulation of the balance between bone formation and resorption
Autophagy plays a vital role in regulating the balance of bone metabolism. An appropriate level of autophagy can maintain the survival and function of bone cells, ensuring the dynamic balance between bone formation and resorption. For example, under low estrogen conditions, autophagy can protect osteoblasts, promoting their proliferation and differentiation, while inhibiting autophagy induces apoptosis of osteoblasts, affecting bone formation13. Meanwhile, autophagy is also involved in the regulation of the formation and function of osteoclasts, thereby affecting bone resorption. In osteoclasts, the deficiency of the autophagy-related gene BECN1 leads to a decrease in osteoclast differentiation and bone resorption capacity, indicating the significant impact of autophagy on the function maintenance of osteoclasts and the process of bone resorption14.
Involvement in bone cell differentiation and maturation
Autophagy is closely related to the differentiation and maturation of bone cells. In the early stage of differentiation of bone marrow mesenchymal stem cells into osteoblasts, the level of autophagy changes, and the expression of autophagy-related genes is coordinated with the process of cell differentiation. Autophagy provides an energy and material basis for cell differentiation by degrading damaged proteins and organelles within the cell, promoting the differentiation and maturation of osteoblasts. At the same time, autophagy is also involved in the regulation of the differentiation and maturation of osteoclast precursors, affecting the function and number of osteoclasts. As a cellular stress response mechanism, autophagy can help bone cells cope with various stress conditions, such as oxidative stress, hypoxia, and nutrient deficiency. Under oxidative stress conditions, autophagy can clear the accumulated reactive oxygen species (ROS) within the cell, reducing oxidative damage and protecting the integrity and function of bone cells. For example, in osteoblasts stimulated by H₂O₂, the activation of autophagy helps to clear ROS, alleviate oxidative damage, and maintain cell survival and activity15. In addition, autophagy is also involved in the adaptive response of cells under hypoxic conditions, helping bone cells survive in a hypoxic environment by regulating energy metabolism and the stability of the intracellular environment16.
Promotion of bone regeneration and repair
Autophagy plays a key role in the process of bone regeneration and repair. During fracture healing, autophagy is involved in the regulation of callus formation and maturation, promoting the regeneration and repair of bone tissue. Studies have shown that some hormones and growth factors affect bone regeneration and repair by regulating autophagy. For example, parathyroid hormone (PTH) can promote autophagy in osteoblasts and chondrocytes, which is beneficial for the relief of osteoarthritis and the repair of bone tissue17,18.
Maintenance of bone cell energy metabolism balance
Autophagy provides energy and metabolic products for bone cells by degrading and recycling substances within the cell, maintaining the energy metabolism balance of the cell. Under conditions of nutrient deficiency or increased energy demand, autophagy can break down large molecules within the cell, such as proteins, lipids, and glycogen, converting them into energy and metabolic intermediates to meet the energy needs of the cell and ensure the normal physiological function of bone cells19,20.
Abnormal changes and key mechanisms of autophagy in the pathogenesis of osteoporosis decline in autophagy function and bone metabolism imbalance
In osteoporosis, cellular autophagy function is abnormal, primarily characterized by decreased autophagy levels or aberrant expression of autophagy-related proteins. This decline in autophagy function disrupts the balance of bone metabolism, leading to an imbalance between bone formation and resorption. For instance, studies have found that the expression levels of autophagy-related proteins are reduced in the bone marrow mesenchymal stem cells of osteoporosis patients, affecting their ability to differentiate into osteoblasts and consequently reducing bone formation21,22,23.
Mechanisms affecting osteoblasts
Estrogen deficiency is one of the significant factors contributing to osteoporosis. It markedly reduces the expression levels of autophagy-related proteins in osteoblasts, such as ATG5 and ATG7, thereby inhibiting osteoblast differentiation and mineralization and increasing osteoblast apoptosis. Additionally, the increase in reactive oxygen species (ROS) is a key factor affecting osteoblast autophagy in osteoporosis. In an oxidative stress environment, excessive ROS can damage intracellular proteins and organelles. The decline in autophagy function fails to clear these damaged substances in a timely manner, further exacerbating oxidative damage to osteoblasts. This ultimately leads to osteoblast apoptosis and functional impairment, affecting bone formation24.
Mechanisms affecting osteoclasts
In osteoporosis, autophagy abnormalities also impact osteoclast function. On the one hand, changes in the expression of autophagy-related proteins may promote osteoclast formation and activation. For example, Zhan19 found that downregulation of certain autophagy-related proteins increases the secretion of receptor activator of nuclear factor-κB ligand (RANKL), a key factor in promoting osteoclast differentiation and activation, thereby accelerating bone resorption. On the other hand, autophagy dysfunction may lead to mitochondrial dysfunction and ROS accumulation in osteoclasts, further enhancing their bone resorption capacity and exacerbating bone loss.
Relationship with Cellular Senescence
Cellular senescence is one of the important mechanisms in the pathogenesis of osteoporosis, and it is closely related to the decline in autophagy function. In senescent bone marrow mesenchymal stem cells, decreased autophagy levels lead to the accumulation of damaged mitochondria and proteins, triggering the senescence-associated secretory phenotype (SASP). This results in the secretion of large amounts of inflammatory factors and matrix metalloproteinases, which not only inhibit osteoblast differentiation and function but also promote osteoclast activation and bone resorption, thereby accelerating the progression of osteoporosis25,26.
Association with Inflammatory Response Osteoporosis is often accompanied by a chronic low-grade inflammatory state, and there is a complex interplay between inflammatory responses and autophagy. Inflammatory cytokines such as TNF-α and IL-1β can affect the initiation and regulation of autophagy through various signaling pathways. Conversely, autophagy dysfunction can also regulate the production and release of inflammatory cytokines. In osteoporosis, increased release of inflammatory cytokines further inhibits osteoblast autophagy and function while promoting osteoclast formation and activation, exacerbating bone metabolism imbalance27,28.
Traditional Chinese Medicine (TCM) interventions in autophagy-related pathways for the treatment of osteoporosis
The PI3K/AKT/mTOR signaling pathway
PI3K can phosphorylate lipids on the cell membrane to produce phosphatidylinositol-3,4,5-trisphosphate (PIP3). AKT, as a downstream effector molecule, undergoes conformational changes and is activated upon sensing PIP3 signals. Activated AKT further phosphorylates downstream mTOR, which, as a key regulator of cell growth and metabolism, promotes the synthesis of cell cycle-related proteins such as cyclin D1, driving the cell cycle transition from the G1 to S phase and accelerating osteoblast proliferation29,30. In addition, mTOR promotes the phosphorylation of key factors for protein synthesis, such as 4E-BP1 and S6K1, enhancing protein synthesis and providing a material basis for osteoblast differentiation, ultimately enhancing osteoblast function and promoting bone tissue formation. For example, Mi et al. found that a kidney-tonifying and blood-activating formula activates this pathway, upregulating the protein expression of PI3K, p-AKT, and mTOR, significantly promoting the expression of bone formation-related genes and proteins, and accelerating bone defect repair31,32.
Activation of AKT can inhibit the expression of apoptosis-related proteins such as Bax. Bax, a pro-apoptotic protein on the mitochondrial outer membrane, can lead to changes in mitochondrial permeability when its expression increases, releasing cytochrome c and activating the caspase enzyme family, thereby inducing cell apoptosis33,34. Activation of AKT reduces Bax expression, preventing this process. Meanwhile, AKT increases the expression of the anti-apoptotic protein Bcl-2, which can compete with Bax for binding to pores on the mitochondrial outer membrane, preventing the release of cytochrome c and thus reducing osteoblast apoptosis and maintaining bone mass34. mTOR is a key negative regulator of autophagy. Under nutrient-rich conditions, mTOR is highly active and can bind to and inhibit the activity of the autophagy-related protein ULK1, preventing autophagy35,36. However, when cells face stress conditions such as nutrient deficiency or hypoxia, mTOR activity is inhibited, ULK1 is activated, and autophagy is initiated. Autophagy can clear damaged mitochondria and proteins within the cell, maintaining intracellular homeostasis. Moderate autophagy helps osteoblasts cope with adverse conditions such as nutrient insufficiency or oxidative stress, thereby protecting bone tissue37,38,39. Niu40 found that a kidney-warming and pain-relieving formula can modulate the AMPK/mTOR signaling pathway, increase autophagy levels, improve bone microstructure, and promote bone tissue repair and regeneration.
AMPK/mTOR signaling pathway
AMPK, a highly conserved Ser/Thr protein kinase, is extremely sensitive to changes in cellular energy status. When cells are confronted with energy deficiency, the AMP/ATP ratio increases, leading to the activation of AMPK. Activated AMPK directly initiates autophagy by phosphorylating autophagy-related proteins such as ULK1, providing critical support for the removal of damaged components and the maintenance of cellular homeostasis41,42. Furthermore, AMPK indirectly enhances autophagy by inhibiting the activity of mTOR. During autophagy, excess glycogen, fat, and proteins within the cell are orderly degraded to supply energy and nutrients for cellular function, ensuring that cells can maintain basic physiological functions under adverse conditions43,44.
In the field of osteoporosis treatment, the activation of the AMPK/mTOR signaling pathway shows great potential. On one hand, AMPK can precisely regulate energy metabolism, providing strong impetus for the proliferation and differentiation of osteoblasts and promoting new bone formation. On the other hand, it can skillfully regulate the expression of osteopontin, a key protein in bone metabolism, accelerating the formation of mineralization nodules and contributing to increased bone density and optimized bone metabolism45,46. For example, a study by Wei47demonstrated that Zanggu Zhitong capsules improve bone density and bone metabolism by modulating the AMPK/mTOR signaling pathway, which may be related to the activation of AMPK and the subsequent regulation of downstream signaling pathways.
Moreover, the activation of AMPK is also highly effective in combating oxidative stress. It can finely regulate the cellular redox state and significantly promote the expression of antioxidant enzymes such as SOD and CAT, thereby reducing the generation of ROS at the source. ROS, as "destructive molecules" within cells, can cause severe damage to biological macromolecules such as DNA, proteins, and lipids when uncontrolled, thereby disrupting normal cellular physiological functions. By precisely inhibiting ROS generation, the activation of AMPK builds a robust antioxidant defense for osteocytes, effectively alleviating oxidative stress damage and maintaining the health and vitality of bone tissue. Compared with other traditional treatments, the activation of the AMPK/mTOR signaling pathway not only regulates energy metabolism and promotes bone formation but also enhances antioxidant stress resistance. This multi-target and comprehensive mechanism of action makes it unique in the treatment of osteoporosis, providing a more promising new strategy for clinical treatment.
The PINK1/Parkin signaling pathway
Under physiological conditions, PINK1, a mitochondrial outer membrane protein, is typically translocated into the mitochondria and degraded by the translocase of the inner mitochondrial membrane. However, when mitochondrial function is impaired and the membrane potential decreases, PINK1 is unable to enter the inner membrane and instead accumulates on the outer membrane. At this point, PINK1 phosphorylates Parkin, promoting its translocation from the cytosol to the mitochondrial surface. As an E3 ubiquitin ligase, Parkin is involved in the ubiquitination of mitochondria, which allows them to be recognized and degraded by autophagosomes, thereby clearing damaged mitochondria and maintaining the normal function of mitochondria within the cell48,49,50.
By promoting mitophagy, the PINK1/Parkin signaling pathway can reduce the production of reactive oxygen species (ROS) from damaged mitochondria within the cell. ROS not only damage intracellular biomacromolecules but also induce apoptosis. Therefore, the activation of the PINK1/Parkin signaling pathway can decrease oxidative stress levels, protect osteocytes from oxidative damage, and maintain cell viability and function51,52.
In the treatment of osteoporosis, modulating the PINK1/Parkin signaling pathway helps restore the balance of bone metabolism. On one hand, by clearing damaged mitochondria, it maintains the health of osteoblasts and enhances their bone formation capacity. On the other hand, reducing ROS production can inhibit the activity of osteoclasts and decrease bone resorption. Xian et al. 53reported that Zuo Gui Wan and You Gui Wan regulate the PINK1/Parkin signaling pathway, affect the level of mitophagy, and thereby modulate bone metabolism, increase bone density, decrease serum osteocalcin levels, and effectively improve postmenopausal osteoporosis symptoms. Compared with traditional treatment methods, this treatment strategy based on signaling pathway regulation focuses more on restoring the balance of bone metabolism at the cellular level and demonstrates unique advantages.
In summary, the PI3K/AKT/mTOR signaling pathway mainly enhances bone formation and reduces bone resorption in the treatment of osteoporosis by promoting the proliferation and differentiation of osteoblasts, inhibiting osteoblast apoptosis, and regulating autophagy function. Activation of this pathway can effectively improve the function of osteoblasts and maintain bone mass. The AMPK/mTOR signaling pathway regulates autophagy by sensing changes in cellular energy status, thereby enhancing bone metabolism and exerting antioxidant stress effects to protect osteocytes from damage. In contrast, the PINK1/Parkin signaling pathway is more focused on clearing damaged mitochondria through mitophagy, reducing oxidative stress, and maintaining the health and normal function of osteocytes to regulate the balance of bone metabolism, providing new targets and mechanisms for the treatment of osteoporosis.
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In summary, autophagy plays a crucial role in the pathogenesis and progression of osteoporosis. Dysregulation of autophagy inevitably disrupts the balance of bone metabolism, negatively impacting the function and number of osteoblasts and osteoclasts (Figure 1), ultimately leading to severe consequences such as bone loss and structural damage.
In stark contrast to the single-target intervention of traditional Western medicine, traditional Chinese ...
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The authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this paper.
Scientific Research Project of Sichuan Provincial Administration of Traditional Chinese Medicine (GrantNos. 2024MS276,25ZDIZX017,2024Ms152);
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