The close relation of the use of glucocorticoid with the occurrence of femoral head necrosis was discovered more than 30 years ago [4]. A retrospective analysis showed that hormone-related nontraumatic ONFH is dominant [1]. Investigating biological characteristics of SONFH at the gene level is an important strategy, and scholars have explored SONFH gene sequencing data combined with bioinformatics. However, these studies also present some defects, such as inability to interpret high-throughput sequencing data correctly to ensure that a certain deviation exists between qRT-PCR verification data and the data significance [10, 22]. The results of this study revealed that hundreds of coding genes, including TNF-a(Tumor Necrosis Factor-A), PI3K-Akt, HIF-1(Hypoxia-inducible Factor-1), adherens junction and MAPK(Mitogen-activated Protein Kinase) signalling pathways, are up-regulated in the peripheral blood of early SONFH patients. These pathways participate in redox, inflammatory response, angiogenesis, and cell metabolism by secreting inflammatory chemokine signalling proteins. The PPI analysis of DEGs showed that PRDX2, HP, MMP8, FPR2 and ITGAX may be associated with the SONFH process. Formyl peptide receptor 2 (FPR2) is a low-affinity receptor of N-formyl methionine peptides and a powerful neutrophil chemokine [23]. FAM19A5(Family with sequence similarity 19 member A5) is a neural factor or brain-specific chemokine that can remarkably reduce the expression level of osteoclast-related genes, such as RANK(Receptor Activator of Nuclear factor Kappa B) and TRAF6(TRAF6), while up-regulation osteoclast-producing negative regulators, such as MafB(Musculoaponeurotic Fibrosarcoma Oncogene Homolog B) and IRF-8(Interferon Regulatory Factor-8) [15, 25]. Inhibition of FAM19A5-inducedosteoclastogenesis can be significantly reversed with FPR2 antagonist WRW4 or FPR2 deficiency, thereby indicating that FPR2 plays an important role in the regulation of osteoclastogenesis and the occurrence and development of SONFH disease [10, 13].
The integrin alpha-X/beta-2 encoded by integrin subunit alpha X (ITGAX) is a receptor that recognises the GPR sequence in fibrinogen, mediates cell–cell interactions during inflammatory responses and is particularly important in monocyte adhesion and chemotaxis [2, 19]. Compared with those of the non-SONFH group, PRDX2 was a thiol-specific peroxidase in down-regulated genes of the SONFH group that can catalyse the reduction of hydrogen peroxide and organic peroxide to produce water and alcohol and result in the inactivation of toxic substances [3]. At the same time, PRDX2 is a hydrogen peroxide-mediated signal transduction sensor that prevents oxidative stress, plays a role in cell protection and likely participates in signal cascade reaction of growth factor and tumour necrosis factor-α by regulating the intracellular concentration of H2O2 [7, 20].
Haptoglobin (HP)-related diseases include haptoglobinemia and Plasmodium falciparum Malaria [16], and related pathways include innate immune system and vesicle-mediated transport. Hemoglobin accumulates in the kidney and is secreted in the urine due to hemolysis. HP will capture and bind to free plasma hemoglobin and thus prevent kidney damage. Haptoglobin also acts as an antioxidant, presents antibacterial activity, and plays a role in many acute phase regulations [17]. Therefore, the down-regulation of PRDX2 and HP may promote the development of SONFH disease through the redox pathway.
MMPs (Matrix metalloproteinases ) are considered the key regulator for maintaining bone homeostasis [14]. MMP-8 (Matrix metallopeptidase 8) from the matrix metalloproteinase family is encoded by the MMP8 gene, also known as neutrophil or PMNL collagenase, which is a collagen lyase that generally exists in mammalian connective tissues. The reduction of collagenase is the premise of effective osteoclast fusion. Inhibition of endogenous collagenase expression or activity can significantly increase osteoclast fusion. The fusion of trap-positive mononuclear osteoclast precursors is essential in the formation of fully functional mature osteoclasts [6]. Moreover, MMP8 deficiency can increase the occurrence of arthritis and bone loss in the serum metastatic arthritis model [5]. In situ hybridisation on rat hindlimb tissue sections revealed the MMP8 gene expression in osteoblast precursor cells, osteoblasts, and chondrocytes during the embryonic development of rat bone and cartilage [18]. Therefore, MMP8 may participate in the disease process of SONFH by affecting the structure and function of osteoblasts and osteoclasts.