Study On The Mechanism Of Gujian Powder Intervention On Steroid-induced Necrosis Of Femoral Head Based On Macrophages And Its Related Pathway

Abstract: Steroid-induced necrosis of the femoral head is a common and refractory disease in orthopedics, which is induced by glucocorticoid and caused by many factors. It is difficult to cure and has a poor curative effect, which has a great impact on the quality of life of patients. Traditional Chinese medicine in treating steroid-induced necrosis of the femoral head can not only improve the symptoms of the disease but also eliminate the root causes of the disease, which has obvious advantages. Wei Guikang, a master of traditional Chinese medicine, summed up the prescription of Gujian Powder based on years of clinical experience, which significantly treats early steroid-induced necrosis of the femoral head. Through literature review and analysis, it is concluded that all Chinese herbs and their effective components in Gujian Powder can participate in the regulation of IL-6, IL-1β, IL-10, TNF-α, iNOS, COX-2 and other important factors related to inflammation by regulating the signal pathways closely related to macrophages, such as NF-κB, Wnt/β-catenin, MAPK, COX, and iNOS. However, because the pathogenesis of steroid-induced necrosis of the femoral head is too complicated at present, this review only expounds on some mechanisms, there are many traditional Chinese medicines in Gujian Powder, and the interaction mechanism of various conventional Chinese medicines among the prescriptions is not clear, so it only expounds some mechanisms of traditional Chinese medicines affecting Steroid-induced necrosis of the femoral head, and themechanism of its prescriptions needs further study

Keywords: Gujian powder; Steroid-induced necrosis of the femoral head; Signal pathway; Research progress

NEW HERBAL FORMULATION HIGH-QUALITY CISTANCHE FOR  STEROID-INDUCED NECROSIS OF THE FEMORAL HEAD

CLICK FOR MORE DETAILS

Steroid-induced necrosis of the femoral head (SNOFH) is a common orthopedic disease that is difficult to treat. Currently, the incidence of non-traumatic femoral head necrosis is high in my country, with nearly 10 million people suffering from this disease. Excessive use of hormones is one of the main causes of non-traumatic femoral head necrosis [1]. Long-term use of hormones can lead to impaired blood supply to the femoral head, destruction of bone cells and bone marrow components, resulting in structural changes in the bone, collapse of the femoral head, and joint dysfunction, ultimately leading to the occurrence of SNOFH [2]. In the course of SNOFH, macrophages can affect the level of inflammation and the balance between OB and OC through multiple pathways [3]. As the course of SNOFH continues to advance, patients will experience symptoms such as hip pain and lower limb movement disorders. As the disease progresses, they may eventually face total hip replacement. However, total hip replacement also has many problems such as high cost, many adverse reactions, and poor patient prognosis.

With the continuous development of traditional Chinese medicine, various traditional Chinese medicines play an important role in the treatment of early SNOFH. Based on the basic theories of traditional Chinese medicine and long-term clinical diagnosis and treatment experience, Wei Guikang, a master of traditional Chinese medicine, summarized classic prescriptions and created a prescription called Gujiansan, which has the effects of nourishing the liver and kidney, removing blood stasis and promoting new blood, for the treatment of SNOFH. The whole prescription of Gujiansan contains 11 Chinese herbs, which means "two monarchs, four ministers and five assistants, which is the middle of the system". The prescription includes deer antler, Panax notoginseng, American ginseng, Cistanche deserticola, saffron, Rhizoma Coptidis, ginger, large bone, small bone, tangerine peel and Rhizoma Cynoglossi. After more than 30 years of clinical application, this prescription has been used to treat tens of thousands of SNOFH patients with good clinical effects. Clinical observation studies have confirmed that the total effective rate of Gujiansan treatment is 93% [4].

This article discusses the mechanism of action of Gujiansan and its active ingredients in regulating macrophages to prevent and treat SNOFH and provides relevant theoretical support for the clinical application of kidney-tonifying and blood-activating prescriptions and related preparations to prevent and treat SNOFH.

1 Pathological mechanism of steroid-induced femoral head necrosis

Currently, the Fiat staging method is generally used clinically to divide femoral head necrosis into five stages. Stage 1 femoral head necrosis has no clear symptoms and signs, while stage 2 is asymptomatic or has only mild hip symptoms and no significant activity restrictions. Stage 3 femoral head necrosis occurs with hip pain, severe lameness, and internal rotation.

Restricted, strong internal rotation causes severe pain. Stage 4 femoral head necrosis presents with moderate to severe pain, severe claudication, and moderate limitation of synovial joint movement. Stage 5 femoral head necrosis presents moderate to severe pain, severe claudication, significantly limited synovial joint movement, and synovial joint deformity. At present, academic circles believe that the generation of SNOFH is caused by a variety of factors. There are many theories, such as the theory of reduced osteogenic ability of bone marrow mesenchymal stem cells (BMSCs), blood deficiency theory, inflammation, and apoptosis. Theory, Non-coding RNA, and Gene Polymorphism Theory

On etc.[1]. After femoral head necrosis, necrotic cells release a large amount of chemokines and cytokines, disrupting the immune balance, and eventually causing irreversible collapse of the femoral head. Macrophages play an important role in promoting and suppressing inflammation levels. At the same time, macrophages are important in maintaining the dynamic balance of OB and OC [5], which shows that macrophages are important in the occurrence and development of steroid-induced femoral head necrosis.

In animal experiments related to SNOFH, glucocorticoids plus lipopolysaccharide (LPS) are often used to induce SNOFH necrosis in animal models. When LPS is combined with hormones, it is easier to induce femoral head necrosis in animals [6]. As an endotoxin, LPS itself is one of the inducing factors of SNOFH. LPS can activate macrophages through the cell signal transduction system in the body, and synthesize and release a variety of cytokines and inflammatory mediators, thereby affecting the immune system and causing vascular disease. damage. When LPS enters the body, lipopolysaccharide-binding protein LBP (lipopolysaccharide-binding protein) can recognize LPS. LBP combines with LPS monomers and is transported to the surface of myeloid-derived cells, where it binds to the LRR structural protein CD14 on the surface of the source cells. , forming the LPS-LBP-CD14 triplet complex.

The triplet is then transported to the complex of Toll-like receptor 4 (TLR4) and myeloid differentiation antigen (MD2). The triplet complex binds to TLR4 with the help of MD-2, activates TLR4, and dimers it [7 ]. After TLR4 is activated, it transmits signals into cells, thereby activating intracellular signaling pathways. After the signal is transmitted into the cell, the adapter molecule myeloid differentiation factor (MyD88) is activated, and IL1R-related protein kinase (IRAK) gathers into the receptor complex through MyD88 and MyD88 adapter protein analogs, phosphorylating and activating IRAK.

IRAK then dissociates from the complex and transmits the signal to tumor necrosis factor receptor-associated factor 6 (TRAF6), causing its activation. Activated TRAF6 conducts signal transduction by activating nuclear factor-κB-inducing kinase (NIK) and transforming growth factor β-activated kinase (TAK1), and ultimately activates the corresponding nuclear factor kappa-B (NF-κB) and filament proteins. Two related inflammatory pathways are mitogen-activated protein kinase (MAPK). Through these two pathways, it ultimately causes the release of IL-1β, IL-1, IL-6, TNF-α, NO, etc., forming an inflammatory response [8], thereby accelerating the progression of SNOFH. See Figure 1.

The polarization of M2 macrophages is mainly induced by IL-4 and IL-13 through IL4Rα activation of phosphorylation of STAT6 (Signal transducer and activator of transcription 6, STAT6)[12]. M2 macrophages can be divided into three subtypes: M2a, M2b, and M2c, and the three subtypes have different functions. M2a is induced by IL-4 or IL-13 and can promote cell growth and tissue repair. M2c, i.e., inactivated macrophages, is induced by hormones, IL-10 or TGF-β, and plays a role in immune regulation and inflammation inhibition. M2b is induced by immune complexes and LPS/IL-1 stimulation, which can increase IL-10 and reduce IL-12 secretion, and play a role in inhibiting the level of inflammation in the acute phase of inflammation[19]. IL-10 can antagonize the pro-inflammatory effects of other cytokines such as TNF-α, IL-1β, etc., thereby playing a role in controlling inflammation. Since TNF-α, IL-1β, etc. can activate TLR4 and the downstream signal p38/MAPK pathway of TLR4. As one of the important branches of the MAPK pathway, the p38/MAPK pathway is closely related to inflammation and cell apoptosis.

When the expression of the p38/MAPK signaling pathway is inhibited, the expression level of OC is also reduced [20], thereby playing a role in maintaining bone homeostasis and bone balance in SNOFH. In SNOFH, when the level of IL-10 rises, it can inhibit the inflammatory response and relieve the joint pain and injury caused by SNOFH [21]. Therefore, IL-10 secreted by macrophages can produce an anti-inflammatory response by reducing the phosphorylation level of p38/MAPK [22], delaying the occurrence and development of SNOFH. The dynamic balance between proinflammatory cytokines TNF-α and IL1β and anti-inflammatory cytokines IL-2, IL-4, and IL-10 is closely related to the level of inflammation. The imbalance of the levels of various proinflammatory cytokines can lead to the occurrence of inflammation-related diseases. The distribution of M1 and M2 macrophages in inflammation can affect the dynamic balance of proinflammatory and anti-inflammatory factors and interfere with the occurrence and development of inflammation.

3 Traditional Chinese medicine and steroid-induced femoral head necrosis

There is no record of the disease name of SNOFH in traditional Chinese medicine. It is usually treated as paralysis. "Suwen·Changcaijie Lun" states: "The disease is in the bones. If the bones are heavy and cannot be lifted, the bone marrow is sore and cold, it is called bone paralysis." "Suwen·Antiology": "If kidney qi is hot, the waist and spine will not lift, the bones will dry up and the marrow will decrease, resulting in bone flaccidity." "spirit

"Shu Jie Zhen Xie No. 75": "The deficiency evil is also cold in the body. Cold and heat compete with each other. If it lasts for a long time, it will be internal. If the cold overcomes the heat, the bones will hurt and the flesh will wither. If the heat overcomes the cold, then Rotten flesh and sloughed muscles turn into pus, and internal injuries to bones turn into bone erosion." Bone paralysis, bone failure, and bone erosion should be the corresponding disease names at different stages in the development of femoral head necrosis, with different pathological changes and different syndrome manifestations. That is, in the early stage, qi blockage and blood vessel occlusion are the basic pathogenesis, which is called It is called bone paralysis. In the late stage, there is collapse and defect of the femoral head, which is called bone erosion. In the early stage and late stage, the empty marrow sea leads to the reduction of bone marrow and bone dryness, which finally makes the muscles and bones flaccid and soft, which is called bone weakness. That is, the early stage is bone paralysis, and the early stage is pain. The middle stage is bone weakness, which is manifested by increased pain and initial reduction of bone marrow. The later stage is bone erosion, which is characterized by muscle decay and bone destruction. In SNOFH, due to long-term use of hormones, the meridians are blocked, Qi and blood are deficient, the marrow sea is empty, the marrow is dead and the bones are withered. At the same time, long-term use of hormones can also cause damage to the liver and kidney yin essence, and the innate essence is damaged.

The day after tomorrow, it will lead to insufficient Qi in the spleen and kidneys, Qi is the commander of blood, and blood is the mother of Qi, eventually leading to blood stasis. Therefore, its pathogenesis is mainly based on kidney deficiency and blood stasis as the underlying symptom. Clinically, it is divided into syndrome types such as liver and kidney deficiency, qi stagnation and blood stasis. Traditional Chinese medicine that activates blood circulation and removes blood stasis can improve microcirculation, regulate blood fluidity and viscosity, increase vascular blood volume, improve the ischemic state of SNOFH, and promote the repair of osteonecrosis areas [23]. Treating SNOFH with the method of nourishing the kidney and warming yang can promote angiogenesis, improve local microcirculation of the femoral head, promote bone hyperplasia, and repair necrotic bone tissue in SNOFH [24]. Therefore, in the actual clinical treatment of SNOFH, traditional Chinese medicine often uses kidney-tonifying and The main treatment method is to activate collaterals and activate blood circulation.