S100 Calcium Binding Protein A9 Represses Angiogenic Activity and Aggravates Osteonecrosis of the Femoral Head.

Re-Wen Wu,Wei-Shiung Lian,Chung-Wen Kuo,Yu-Shan Chen,Feng-Sheng Wang,Jih-Yang Ko

doi:10.3390/ijms20225786

Abstract

Ischemic damage aggravation of femoral head collapse is a prominent pathologic feature of osteonecrosis of the femoral head (ONFH). In this regard, S100 calcium binding protein A9 (S100A9) is known to deteriorate joint integrity, however, little is understood about which role S100A9 may play in ONFH. In this study, a proteomics analysis has revealed a decrease in the serum S100A9 level in patients with ONFH upon hyperbaric oxygen therapy. Serum S100A9 levels, along with serum vascular endothelial growth factor (VEGF), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-6 (IL-6), and tartrate-resistant acid phosphatase 5b levels were increased in patients with ONFH, whereas serum osteocalcin levels were decreased as compared to healthy controls. Serum S100A9 levels were increased with the Ficat and Arlet stages of ONFH and correlated with the patients with a history of being on glucocorticoid medication and alcohol consumption. Osteonecrotic tissue showed hypovasculature histopathology together with weak immunostaining for vessel marker CD31 and von Willrbrand factor (vWF) as compared to femoral head fracture specimens. Thrombosed vessels, fibrotic tissue, osteocytes, and inflammatory cells displayed strong S100A9 immunoreactivity in osteonecrotic lesion. In vitro, ONFH serum and S100A9 inhibited the tube formation of vessel endothelial cells and vessel outgrowth of rat aortic rings, whereas the antibody blockade of S100A9 improved angiogenic activities. Taken together, increased S100A9 levels are relevant to the development of ONFH. S100A9 appears to provoke avascular damage, ultimately accelerating femoral head deterioration through reducing angiogenesis. This study provides insight into the molecular mechanism underlying the development of ONFH. Here, analysis also highlights that serum S100A9 is a sensitive biochemical indicator of ONFH.

Highlights

Osteonecrosis of the femoral head (ONFH) is a progressive damage of hip microarchitecture together with catastrophic pain and lower limb disability [1], terribly devastating patients activity and even psychology [2], becoming a major cause of hip arthroplasty [3]
This study aims to investigate whether serum S100 calcium binding protein A9 (S100A9) is relevant to human ONFH and reveal that role which S100A9 may play in vessel formation in femoral head osteonecrotic tissue
Eight proteins homologues to filamin A (FLNA), gelsolin isoform B, disulfide isomerase-associated 3 isoform 1, annexin III chain III, and capping protein muscle Z-line-β were increased upon hyperbaric oxygen therapy (HBO) therapy, whereas 3 proteins homologues to actin beta (ACTB) protein and S100A9 were reduced (Figure 1B), as evident from the tandem mass spectrometry (Figure 1C and Table 1)

Summary

Introduction

Osteonecrosis of the femoral head (ONFH) is a progressive damage of hip microarchitecture together with catastrophic pain and lower limb disability [1], terribly devastating patients activity and even psychology [2], becoming a major cause of hip arthroplasty [3]. Marrow edema, bone cell death, and femoral head collapse are prominent histopathologic features of the hip disorder. In experimental ONFH models, the dephosphorylation of elF2, an endoplasmic reticulum stress regulator, increases angiogenic factor vascular endothelial growth factor (VEGF) production and angiogenesis, slowing femoral head injury during the surgery-mediated ONFH [10]. Epigenetic regulator microRNA-34a is important to inhibit glucocorticoid excess-induced endothelial cell dysfunction and vessel loss in rats with femoral head osteonecrosis [11]. The decreased bone marrow mesenchymal stem cell-derived microRNA-224-3p enhances angiogenic activity in cases of traumatic ONFH [12]. Overactivated toll-like receptor 4 (TLR4) and the nuclear factor-κB (NF-κB) signaling pathways suppress angiogenesis in rats with methylprednisolone and endotoxin lipopolysaccharide-mediated avascular necrosis of the femoral head [14]

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