Ischemic necrosis of the femoral head is a pressing problem in the world of medicine and is known as the “coronary heart disease of the hip joint”. The natural course of ischemic necrosis of the femoral head includes two aspects, namely progressive collapse of the femoral head and secondary osteoarthritis of the hip joint. According to the etiology of ischemic necrosis of the femoral head, it can be divided into traumatic and non-traumatic; due to the common abuse of corticosteroids in China, the incidence of Steroid-induced Avascular Necrosis of the Femoral Head (SANFH) has taken the first place in non-traumatic ischemic necrosis of the femoral head clinically. The most studied causative factors are long-term use of glucocorticoids and alcohol consumption, followed by various causes of hypercoagulation, hypofibrinolysis, hyperlipidemia, red blood cell abnormalities, decompression sickness, human immunodeficiency virus infection, smoking and genetic factors. There are several theories of pathogenesis, including microcirculatory embolism and bone marrow cell hypertrophy caused by thrombus, fat, abnormal red blood cells, nitrogen, etc.; the process of femoral head necrosis caused by each theory is similar, manifesting as necrosis of bone cells and bone marrow cells after ischemia. The pathogenesis of femoral head necrosis is complex and cannot be explained by a single doctrine, but should be considered as the same final manifestation of different diseases with multifactorial and multi-stage pathogenesis. At present, among the many theories of hormonal osteonecrosis, the disorder of fat metabolism theory is more generally accepted. The adipose tissue is not only composed of adipocytes, but also includes important cells of the immune system, such as macrophages; adipose tissue proliferation and macrophage infiltration in the bone marrow of the femoral head with lipodystrophy, and the interaction between macrophages and adipose tissue lead to microcirculatory disorders in the femoral head, tissue ischemia, hypoxia, and water swelling, which aggravate the intramedullary hypertension and form a vicious circle, eventually leading to ischemia and necrosis of the femoral head. Adipose tissue macrophages (ATMs) are locally activated in response to a variety of inflammatory and immune stimuli; they are broadly classified into two categories according to their function after activation: classical activated macrophage (M1 type) and alternative activated macrophage (M2 type). macrophage (M1 type) and alternative activated macrophage (M2 type). The two types of cells have significant differences in cell surface receptor expression, cytokine and chemotactic factor release, effector function and intracellular signal transduction, etc. They are involved in different stages of the development of femoral head necrosis and damage repair, and thus play different roles. I. Disorders of lipid metabolism and hormonal osteonecrosis Hormonal ischemic necrosis of the femoral head in patients with proximal bone marrow progenitor cells fat differentiation, adipocyte proliferation, hypertrophy, increased intramedullary pressure, compression of the bone microvascular structure, resulting in impaired circulation and reduced blood flow; marrow tissue ischemia and edema, bone cells die of hypoxia; because bone is a closed chamber, tissue edema to further increase the pressure in the bone marrow, forming a The vicious circle leads to ischemia and necrosis of bone cells. The early pathological changes of osteonecrosis are nuclear consolidation of bone cells, increased empty bone sockets, and a large number of small adipocytes in the bone marrow cavity; in the late stage, a large amount of adipose tissue can be seen filling in the necrotic bone marrow and bone cells, and the adipocytes are hypertrophic and hyperplastic. Therefore, hormones can lead to hypertrophy and accumulation of bone marrow adipocytes in the necrotic area and stimulate a series of pathophysiological responses; the type and distribution of adipocytes, proliferation and apoptosis, storage and transport can be accompanied by imbalance of adipose homeostasis, which leads to ischemic necrosis of bone tissue. The extent of extravascular deposition of adipose tissue depends on both local adipose tissue differentiation occurrence and lipid transport, and an abnormality in either of them can lead to an unexpected event. Adipocytes and osteoblasts are derived from bone marrow stromal cells, and they are genetically homologous and can transdifferentiate from each other under certain conditions; hormones downregulate the gene expression of osteoblast transcriptional differentiation factor while downregulating the gene expression of adipocyte transcriptional differentiation factor, resulting in increased lipogenic differentiation of bone marrow mesenchymal cells, while osteogenic differentiation is inhibited, and necrotic bone cannot be effectively repaired. Zhang et al. showed that hormones decreased the expression of osteogenic genes and proteins through Wnt signaling-related genes and increased the expression of adipogenic genes and proteins. expression of adipogenesis-related genes and proteins. Peroxisome proliferator- activated receptors (PPARs) are a family of transcriptional molecules that regulate lipid metabolism in the nucleus, with PPAR-γ playing a critical regulatory role in adipocyte differentiation. In the early stage of hormonal ischemic necrosis of the femoral head, PPAR-γ gene expression levels were significantly increased and were highly correlated with the proliferation of adipocyte-positive clones. The upregulation of PPAR-γ expression in the necrotic femoral head was accompanied by the inhibition of BMP2 expression; the enhanced differentiation of lipid lineage direction caused a large number of adipocytes generation in the bone marrow and the accumulation and hypertrophy of adipocytes; at the same time, the production of bone lineage cells was reduced, and the speed and quantity of new bone could not compensate for the normal function of the necrotic bone area; further aggravating osteonecrosis and forming a vicious circle. In addition, studies have also confirmed that hormonal osteonecrosis is accompanied by disorders of lipid metabolism and transport disorders, and the use of lipid scavengers can prevent the occurrence of hormonal osteonecrosis. Therefore, during the pathogenesis of hormonal osteonecrosis, enhanced lipid differentiation occurs, lipid transport is diminished, and adipocytes accumulate abnormally, stimulating a series of pathophysiological reactions that lead to ischemic necrosis of bone tissue. Second, ATMs and the inflammatory response Macrophages can be present in any tissue in the body and are the major leukocyte subpopulation in adipose tissue. With the continuous deposition of adipocytes and gradual increase in cell size, adipocytes malfunction and release some inflammatory factors, such as tumor necrosis factor a (TNF-a). TNF-a binds to the surface receptors of hypertrophic adipocytes and regulates the inflammatory response through the dependent NF-κB signaling pathway and MAPK signaling pathway. On the one hand, inflammatory factors attract macrophages to continuously accumulate and infiltrate into adipose tissue; on the other hand, Adipose Tissue Macrophages (ATMs ) themselves release more inflammatory factors, such as TNF-a, IL-6 and IL-12, which promote monocytes and inflammatory cells to infiltrate into adipose tissue. Adipocytes and macrophages establish a paracrine loop through their respective secretion of saturated fatty acids and TNF-a, forming a vicious circle that upregulates the expression of the pro-inflammatory adipocytic factors MCP-1 and TNF-a and downregulates the expression of the anti-inflammatory factor adiponectin; gradually worsening the adipose tissue inflammatory response. The activity of ATMs affects the whole process of adipose tissue development, such as adipocyte differentiation, lipid metabolism, angiogenesis and hypoxic reactivity, and plays an important role in the pathology of hormonal osteonecrosis. They play an important role in the pathogenesis of hormonal osteonecrosis. Adipose tissue macrophages (ATMs) are plastic cells that receive different stimuli and can differentiate into different types of macrophages. Based on the functional characteristics of activated macrophages, ATMs can be divided into two categories: classical activated macrophage (M1 type) and alternative activated macrophage (M2 type). F4/80 is a specific marker on the surface of murine macrophages, CD11c and CD206 are specific markers for M1 and M2 ATMs, respectively, and M1/M2 ATMs can be distinguished based on their surface-specific molecules, i.e. F4/80+/CD11c+/CD206- cells are M1 ATMs, F4/80+/CD11c -/CD206+ cells are M1 ATMs, and F4/80+/CD11c -/CD206+ cells are M2 ATMs. -/M1-type macrophages express high IL-12 and IL-23 and low IL-10, secrete inflammatory cytokines such as TNF-α, IL-1β and IL-6, and participate in antigen presentation; they express iNOS and ROS, promote the synthesis of reactive oxygen species such as NO, and participate in the inflammatory response and clearance of pathogens; M2 type macrophages have low expression of IL-12 and IL-23, but high expression of inflammatory inhibitory factors IL-10, IL-1 neutralizing receptor (decoy receptor), TGF-β, scavenger receptor, mannose receptor, galactose receptor, and arginase (Arginase Ⅰ, Arg1), which inhibit inflammatory response and promote tissue damage repair.M1 type and M1-type and M2-type cells differ significantly in cell surface receptor expression, cytokine and chemotactic factor release, effector function, and intracellular signal transduction, etc. M1-type macrophages promote the inflammatory response and facilitate the clearance of pathogenic microorganisms; M2-type macrophages have the opposite effect, inhibiting the inflammatory response and promoting damage repair. Therefore, the polarity change of ATMs directly affects the inflammatory reactivity of local tissues and participates in various pathophysiological processes, thus stimulating a series of pathophysiological responses and playing an important role in the development of diseases. Third, inflammatory lesions and osteonecrosis The process of osteonecrosis, which is the process of inflammatory reactivity. The early inflammatory response is mild, and its hallmark changes are bone marrow fibrosis and moderate inflammatory cell infiltration; the late inflammatory response is severe, manifested by massive inflammatory cell infiltration, osteocyte apoptosis and bone trap cell vacuity, and the lesion worsens with increasing inflammation [16]. Bone marrow edema is one of the early manifestations of femoral head necrosis and can occur after ischemia, and bone marrow edema can also compress blood vessels leading to ischemia.Jone et al [17] suggested that bone marrow edema is a secondary response to tissue ischemia, and reperfusion secondary to femoral head ischemia leads to reactive tissue congestion, and acute ischemia leads to exudation due to prompt inflammatory response and increased cytokine production (especially IL-1 ) also exacerbate edema. Other clinical studies have also confirmed this, with Iida [18] and Koo et al [19] suggesting that the appearance and increase in the extent of bone marrow edema suggests further progression of osteonecrosis and increased local inflammatory reactivity. Statins have a unique anti-inflammatory effect through which the process of femoral head necrosis can be significantly improved. Statins can significantly reduce a variety of inflammatory transmitters in patients, inhibit the expression of inflammatory cytokines, chemokines and adhesion molecules, correct the systemic dyslipidemia in hormonal osteonecrosis and reduce the damage to the vascular endothelium and osteocytes caused by the inflammatory response in the femoral head. The anti-inflammatory effects of statins reduce tissue damage by reducing adhesion between monocytes and endothelial cells, and by reducing intravascular monocyte chemotactic proteins and tumor necrosis factors that effectively reduce infiltration of leukocytes (especially neutrophils) into the inflamed area. These studies suggest that controlling the local inflammatory response can reduce the development of osteonecrosis. C-reactive protein (CRP) is an important marker of the inflammatory response, and changes in CRP plasma concentration are closely related to the process of inflammation and tissue necrosis, which is an ideal acute phase protein; more and more studies have confirmed that CRP induces endothelial cell dysfunction, damages blood vessel walls, and promotes inflammatory response, and it is closely related to the occurrence, development, and prognosis of ischemic injury. It is closely related to the occurrence, development and prognosis of ischemic injury. Li Guibo et al. investigated the pathogenesis of hormonal osteonecrosis by establishing an animal model of hormonal osteonecrosis and confirmed that the hormonal model group had lower HDL levels and higher CRP levels than the normal control group. TNF-α, produced by activated macrophages and monocytes, is a class of pro-inflammatory cytokines that is the initiator of the cascade of other pro-inflammatory cytokines and can contribute to the production of other pro-inflammatory cytokines such as IL-1, IL-6 and IL-8. Clinical and animal experiments have confirmed that during the development of hormonal femoral head necrosis, serum TNF-α concentration increases and TNF-α expression in the bone marrow tissue of the femoral head is significantly enhanced; this indicates that local inflammation and immune response play an extremely important role in femoral head ischemic necrosis. IV. Regulation of ATMs and osteonecrosis As the course of osteonecrosis progresses, adipocytes continue to accumulate, the inflammatory response is strengthened, and the infiltration of ATMs in the lesion area is increasing; the polarity change of ATMs affects the development of the lesion, and if M1-type macrophages dominate (classical activation), the inflammatory response is further strengthened, promoting the development of osteonecrosis; if M2-type macrophages dominate (alternative activation), the inflammatory response in the osteonecrotic area can be suppressed and the regenerative repair of the necrotic area tissue can be promoted. In addition, adipose tissue macrophages (ATMs) can inhibit stromal cell lipogenic differentiation and thus may play a role in limiting the expansion of adipose tissue. Therefore, adipose tissue macrophages (ATMs) are closely related to the pathogenesis of hormonal femoral head; ATMs alternative activation plays an important role in inhibiting osteonecrosis and promoting the repair of damaged tissues; ATMs alternative activation and regulation may become a new regulatory target for osteonecrosis treatment. The growth and activation of ATMs depend on the involvement of cytokines and the interstitial response of hematopoietic organs. The activation pathway due to interferon-γ (IFN-γ) and lipopolysaccharide (LPS) induction becomes the classical activation, i.e., activation of M1-type cells; IL-4 and IL-13 are typical triggers for alternative activation of macrophages, and alternative activated macrophages can specifically express some immunosuppressive factors, such as Arginase1, IL-10, IL-1RA, etc. IL-4 and IL-13 are typical triggers for alternative activation of macrophages. -IL-4 is produced by activated CD4+ T cells, granulocytes, and mast cells, with the Th2 cell subpopulation being the main source of IL-4. IL-4 binds to the cell surface receptor IL-4Rα and promotes its dimerization into type I or type II receptors, triggering a downstream signaling cascade, which includes the following signaling pathways: Janus kinase family STAT6 (JAK-STAT6) signaling pathway, insulin receptor family-phosphatidylinositol 3-kinase (IRS2-PI3K) signaling pathway, and ultimately by inhibiting the secretion of pro-inflammatory cytokines and upregulating the expression of immunosuppressive cytokines. The importance of alternative macrophage activation for host resistance has been demonstrated in myeloid cell-specific knockout animal models. Interleukin-4 (IL-4) induces alternative activation of macrophages and enhances their phagocytosis and expression levels of histocompatibility complex class II molecules, which provides an excellent tool to study alternative activation of ATMs and their role in disease. Therefore, the correlation between the infiltration distribution and polarization of M1/M2 ATMs in the osteonecrosis area and the occurrence of osteonecrosis; the important role of alternative activation of ATMs in inhibiting osteonecrosis and promoting the repair of damaged tissues; the in-depth study of alternative activation and functional regulation of ATMs can further investigate the pathogenesis of hormonal femoral head necrosis, and provide a new platform for clinical treatment, related drug development and screening. The study of the alternative activation and functional control of ATMs can further investigate the pathogenesis of hormonal osteonecrosis and open up new avenues for clinical treatment, drug development and screening platforms.