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Original Article | Open Access

FAR591 promotes the pathogenesis and progression of SONFH by regulating Fos expression to mediate the apoptosis of bone microvascular endothelial cells

Fei Zhang1,2, Lei Wei3, Lei Wang2, Tao Wang2, Zhihong Xie2, Hong Luo2, Fanchao Li2, Jian Zhang1,2, Wentao Dong1,2, Gang Liu1,2, Qinglin Kang4, Xuesong Zhu5, Wuxun Peng1,2 ( )
Department of Emergency Orthopedics, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China
School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou 550004, China
Department of Orthopedics, Rhode Island Hospital, Brown University, Providence, Rhode Island 02903, USA
Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, China
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Abstract

The specific pathogenesis of steroid-induced osteonecrosis of the femoral head (SONFH) is still not fully understood, and there is currently no effective early cure. Understanding the role and mechanism of long noncoding RNAs (lncRNAs) in the pathogenesis of SONFH will help reveal the pathogenesis of SONFH and provide new targets for its early prevention and treatment. In this study, we first confirmed that glucocorticoid (GC)-induced apoptosis of bone microvascular endothelial cells (BMECs) is a pre-event in the pathogenesis and progression of SONFH. Then, we identified a new lncRNA in BMECs via lncRNA/mRNA microarray, termed Fos-associated lincRNA ENSRNOT00000088059.1 (FAR591). FAR591 is highly expressed during GC-induced BMEC apoptosis and femoral head necrosis. Knockout of FAR591 effectively blocked the GC-induced apoptosis of BMECs, which then alleviated the damage of GCs to the femoral head microcirculation and inhibited the pathogenesis and progression of SONFH. In contrast, overexpression of FAR591 significantly promoted the GC-induced apoptosis of BMECs, which then aggravated the damage of GCs to the femoral head microcirculation and promoted the pathogenesis and progression of SONFH. Mechanistically, GCs activate the glucocorticoid receptor, which translocates to the nucleus and directly acts on the FAR591 gene promoter to induce FAR591 gene overexpression. Subsequently, FAR591 binds to the Fos gene promoter (–245~–51) to form a stable RNA:DNA triplet structure and then recruits TATA-box binding protein associated factor 15 and RNA polymerase Ⅱ to promote Fos expression through transcriptional activation. Fos activates the mitochondrial apoptotic pathway by regulating the expression of Bcl-2 interacting mediator of cell death (Bim) and P53 upregulated modulator of apoptosis (Puma) to mediate GC-induced apoptosis of BMECs, which leads to femoral head microcirculation dysfunction and femoral head necrosis. In conclusion, these results confirm the mechanistic link between lncRNAs and the pathogenesis of SONFH, which helps reveal the pathogenesis of SONFH and provides a new target for the early prevention and treatment of SONFH.

References

1

Fu, W., Liu, B., Wang, B. & Zhao, D. Early diagnosis and treatment of steroid-induced osteonecrosis of the femoral head. Int. Orthop. 43, 1083–1087 (2019).
Crossref Google Scholar
2

Li, Z. et al. Circulating microRNA signature of steroid-induced osteonecrosis of the femoral head. Cell Prolif. 51, e12418 (2018).
Crossref Google Scholar
3

Wang, A., Ren, M. & Wang, J. The pathogenesis of steroid-induced osteonecrosis of the femoral head: a systematic review of the literature. Gene 671, 103–109 (2018).
Crossref Google Scholar
4

Maruyama, M. et al. The effects of a functionally-graded scaffold and bone marrow- derived mononuclear cells on steroid-induced femoral head osteonecrosis. Biomaterials 187, 39–46 (2018).
Crossref Google Scholar
5

Li, T. et al. Discovery and validation an eight-biomarker serum gene signature for the diagnosis of steroid-induced osteonecrosis of the femoral head. Bone 122, 199–208 (2019).
Crossref Google Scholar
6

Jiang, L. Y., Yu, X. & Pang, Q. J. Research in the precaution of recombinant human erythropoietin to steroid-induced osteonecrosis of the rat femoral head. J. Int. Med. Res. 45, 1324–1331 (2017).
Crossref Google Scholar
7

Chang, C., Greenspan, A. & Gershwin, M. E. The pathogenesis, diagnosis and clinical manifestations of steroid-induced osteonecrosis. J. Autoimmun. 110, 102460 (2020).
Crossref Google Scholar
8

Kerachian, M. A., Séguin, C. & Harvey, E. J. Glucocorticoids in osteonecrosis of the femoral head: a new understanding of the mechanisms of action. J. Steroid Biochem. Mol. Biol. 114, 121–128 (2009).
Crossref Google Scholar
9

Zuo, R. et al. Exosomes derived from human CD34(+) stem cells transfected with miR-26a prevent glucocorticoid-induced osteonecrosis of the femoral head by promoting angiogenesis and osteogenesis. Stem Cell Res. Ther. 10, 321 (2019).
Crossref Google Scholar
10

Ramasamy, S. K., Kusumbe, A. P., Wang, L. & Adams, R. H. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature 507, 376–380 (2014).
Crossref Google Scholar
11

Yang, M. et al. MiR-497~195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1α activity. Nat. Commun. 8, 16003 (2017).
Crossref Google Scholar
12

Zhu, S. et al. Endothelial cells produce angiocrine factors to regulate bone and cartilage via versatile mechanisms. Theranostics 10, 5957–5965 (2020).
Crossref Google Scholar
13

Filipowska, J., Tomaszewski, K. A., Niedźwiedzki, Ł., Walocha, J. A. & Niedźwiedzki, T. The role of vasculature in bone development, regeneration and proper systemic functioning. Angiogenesis 20, 291–302 (2017).
Crossref Google Scholar
14

Krüger-Genge, A., Blocki, A., Franke, R. P. & Jung, F. Vascular endothelial cell biology: an update. Int. J. Mol. Sci. 20, 4411 (2019).
Crossref Google Scholar
15

Falkenberg, K. D., Rohlenova, K., Luo, Y. & Carmeliet, P. The metabolic engine of endothelial cells. Nat. Metab. 1, 937–946 (2019).
Crossref Google Scholar
16

Hassanshahi, M., Hassanshahi, A., Khabbazi, S., Su, Y. W. & Xian, C. J. Bone marrow sinusoidal endothelium: damage and potential regeneration following cancer radiotherapy or chemotherapy. Angiogenesis 20, 427–442 (2017).
Crossref Google Scholar
17

Zuo, W., Guo, W. S., Yu, H. C., Liu, P. & Zhang, Q. D. Role of junction-mediating and regulatory protein in the pathogenesis of glucocorticoid-induced endothelial cell lesions. Orthop. Surg. 12, 964–973 (2020).
Crossref Google Scholar
18

Huang, Z., Wang, Q., Zhang, T., Fu, Y. & Wang, W. Hyper-activated platelet lysates prevent glucocorticoid-associated femoral head necrosis by regulating autophagy. Biomed. Pharmacother. 139, 111711 (2021).
Crossref Google Scholar
19

Prisby, R. D. Bone marrow microvasculature. Compr. Physiol. 10, 1009–1046 (2020).
Crossref Google Scholar
20

McCarthy, I. The physiology of bone blood flow: a review. J. Bone Jt. Surg. Am. 88(Suppl 3), 4–9 (2006).
Crossref Google Scholar
21

Zhang, Q., Jin, L. V. & Jin, L. Role of coagulopathy in glucocorticoid-induced osteonecrosis of the femoral head. J. Int. Med. Res. 46, 2141–2148 (2018).
Crossref Google Scholar
22

Zhang, Y., Yin, J., Ding, H., Zhang, C. & Gao, Y. S. Vitamin K2 ameliorates damage of blood vessels by glucocorticoid: a potential mechanism for its protective effects in glucocorticoid- induced osteonecrosis of the femoral head in a rat model. Int. J. Biol. Sci. 12, 776–785 (2016).
Crossref Google Scholar
23

Clarisse, D., Offner, F. & De Bosscher, K. Latest perspectives on glucocorticoid-induced apoptosis and resistance in lymphoid malignancies. Biochim. Biophys. Acta Rev. Cancer 1874, 188430 (2020).
Crossref Google Scholar
24

Dirks-Naylor, A. J. & Griffiths, C. L. Glucocorticoid-induced apoptosis and cellular mechanisms of myopathy. J. Steroid Biochem. Mol. Biol. 117, 1–7 (2009).
Crossref Google Scholar
25

Schmidt, S. et al. Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance. Cell Death Differ. 11(Suppl 1), S45–S55 (2004).
Crossref Google Scholar
26

Jing, D. et al. Opposing regulation of BIM and BCL2 controls glucocorticoid-induced apoptosis of pediatric acute lymphoblastic leukemia cells. Blood 125, 273–283 (2015).
Crossref Google Scholar
27

Ploner, C. et al. The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia. Leukemia 22, 370–377 (2008).
Crossref Google Scholar
28

Zhan, J. et al. Allicin inhibits osteoblast apoptosis and steroid-induced necrosis of femoral head progression by activating the PI3K/AKT pathway. Food Funct. 11, 7830–7841 (2020).
Crossref Google Scholar
29

Kopp, F. & Mendell, J. T. Functional classification and experimental dissection of long noncoding RNAs. Cell 172, 393–407 (2018).
Crossref Google Scholar
30

Sanchez Calle, A., Kawamura, Y., Yamamoto, Y., Takeshita, F. & Ochiya, T. Emerging roles of long non-coding RNA in cancer. Cancer Sci. 109, 2093–2100 (2018).
Crossref Google Scholar
31

Orom, U. A. & Shiekhattar, R. Noncoding RNAs and enhancers: complications of a long-distance relationship. Trends Genet. 27, 433–439 (2011).
Crossref Google Scholar
32

Romero-Barrios, N., Legascue, M. F., Benhamed, M., Ariel, F. & Crespi, M. Splicing regulation by long noncoding RNAs. Nucleic Acids Res. 46, 2169–2184 (2018).
Crossref Google Scholar
33

Ali, T. & Grote, P. Beyond the RNA-dependent function of LncRNA genes. Elife 9, e60583 (2020).
Crossref Google Scholar
34

Kazimierczyk, M., Kasprowicz, M. K., Kasprzyk, M. E. & Wrzesinski, J. Human long noncoding RNA interactome: detection, characterization and function. Int. J. Mol. Sci. 21, 1027 (2020).
Crossref Google Scholar
35

Noh, J. H., Kim, K. M., McClusky, W. G., Abdelmohsen, K. & Gorospe, M. Cytoplasmic functions of long noncoding RNAs. Wiley Interdiscip. Rev. RNA 9, e1471 (2018).
Crossref Google Scholar
36

Shin, T. J., Lee, K. H. & Cho, J. Y. Epigenetic mechanisms of LncRNAs binding to protein in carcinogenesis. Cancers 12, 2925 (2020).
Crossref Google Scholar
37

Zhang, H., Xu, H. B., Kurban, E. & Luo, H. W. LncRNA SNHG14 promotes hepatocellular carcinoma progression via H3K27 acetylation activated PABPC1 by PTEN signaling. Cell Death Dis. 11, 646 (2020).
Crossref Google Scholar
38

Arab, K. et al. Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A. Mol. Cell 55, 604–614 (2014).
Crossref Google Scholar
39

Lan, T. et al. KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3. Mol. Cancer 18, 186 (2019).
Crossref Google Scholar
40

Zhang, F. et al. LncRNA CRNDE attenuates chemoresistance in gastric cancer via SRSF6-regulated alternative splicing of PICALM. Mol. Cancer 20, 6 (2021).
Crossref Google Scholar
41

Han, M. et al. Exosome-mediated lncRNA AFAP1-AS1 promotes trastuzumab resistance through binding with AUF1 and activating ERBB2 translation. Mol. Cancer 19, 26 (2020).
Crossref Google Scholar
42

Wu, Z. et al. LncRNA-N1LR enhances neuroprotection against ischemic stroke probably by inhibiting p53 phosphorylation. Mol. Neurobiol. 54, 7670–7685 (2017).
Crossref Google Scholar
43

Li, L. et al. Bone marrow mesenchymal stem cell-derived exosomes promote plasminogen activator inhibitor 1 expression in vascular cells in the local microenvironment during rabbit osteonecrosis of the femoral head. Stem Cell Res Ther. 11, 480 (2020).
Crossref Google Scholar
44

Chen, C. Y. et al. Extracellular vesicles from human urine-derived stem cells inhibit glucocorticoid-induced osteonecrosis of the femoral head by transporting and releasing pro-angiogenic DMBT1 and anti-apoptotic TIMP1. Acta Biomater. 111, 208–220 (2020).
Crossref Google Scholar
45

Yao, X. et al. PTEN inhibitor VO-OHpic attenuates GC-associated endothelial progenitor cell dysfunction and osteonecrosis of the femoral head via activating Nrf2 signaling and inhibiting mitochondrial apoptosis pathway. Stem Cell Res Ther. 11, 140 (2020).
Crossref Google Scholar
46

Chen, C. et al. Impairment of two types of circulating endothelial progenitor cells in patients with glucocorticoid-induced avascular osteonecrosis of the femoral head. Jt. Bone Spine 80, 70–76 (2013).
Crossref Google Scholar
47

Yu, H. et al. Icariin promotes angiogenesis in glucocorticoid-induced osteonecrosis of femoral heads: in vitro and in vivo studies. J. Cell Mol. Med. 23, 7320–7330 (2019).
Crossref Google Scholar
48

Jing, X. et al. Desferoxamine protects against glucocorticoid-induced osteonecrosis of the femoral head via activating HIF-1alpha expression. J. Cell Physiol. 235, 9864–9875 (2020).
Crossref Google Scholar
49

Dykes, I. M. & Emanueli, C. Transcriptional and post-transcriptional gene regulation by long non-coding RNA. Genom. Proteom. Bioinforma. 15, 177–186 (2017).
Crossref Google Scholar
50

Zhang, X. et al. Mechanisms and functions of long non-coding RNAs at multiple regulatory levels. Int. J. Mol. Sci. 20, 5573 (2019).
Crossref Google Scholar
51

Li, P. et al. Inhibition of long noncoding RNA HIF1A-AS2 confers protection against atherosclerosis via ATF2 downregulation. J. Adv. Res. 26, 123–135 (2020).
Crossref Google Scholar
52

Cheng, D. et al. LncRNA HOTAIR epigenetically suppresses miR-122 expression in hepatocellular carcinoma via DNA methylation. EBioMedicine 36, 159–170 (2018).
Crossref Google Scholar
53

Zhu, L. et al. Impaired autophagic degradation of lncRNA ARHGAP5-AS1 promotes chemoresistance in gastric cancer. Cell Death Dis. 10, 383 (2019).
Crossref Google Scholar
54

Wang, F. W. et al. APC-activated long noncoding RNA inhibits colorectal carcinoma pathogenesis through reduction of exosome production. J. Clin. Investig. 129, 727–743 (2019).
Crossref Google Scholar
55

Malakar, P. et al. Long noncoding RNA MALAT1 regulates cancer glucose metabolism by enhancing mTOR-mediated translation of TCF7L2. Cancer Res. 79, 2480–2493 (2019).
Crossref Google Scholar
56

Yu, Y. et al. LncRNA TUG1 promoted osteogenic differentiation through promoting bFGF ubiquitination. Vitr. Cell Dev. Biol. Anim. 56, 42–48 (2020).
Crossref Google Scholar
57

Kong, L. et al. CPC: assess the protein-coding potential of transcripts using sequence features and support vector machine. Nucleic Acids Res. 35, W345–W349 (2007).
Crossref Google Scholar
58

Wright, M. W. A short guide to long non-coding RNA gene nomenclature. Hum. Genom. 8, 7 (2014).
Crossref Google Scholar
59

Akhter, R., Sanphui, P., Das, H., Saha, P. & Biswas, S. C. The regulation of p53 up-regulated modulator of apoptosis by JNK/c-Jun pathway in beta-amyloid-induced neuron death. J. Neurochem. 134, 1091–1103 (2015).
Crossref Google Scholar
60

Eferl, R. & Wagner, E. F. AP-1: a double-edged sword in tumorigenesis. Nat. Rev. Cancer 3, 859–868 (2003).
Crossref Google Scholar
61

Springhower, C. E., Rosen, M. K. & Chook, Y. M. Karyopherins and condensates. Curr. Opin. Cell Biol. 64, 112–123 (2020).
Crossref Google Scholar
62

Janke, A. M. et al. Lysines in the RNA polymerase Ⅱ C-terminal domain contribute to TAF15 fibril recruitment. Biochemistry 57, 2549–2563 (2018).
Crossref Google Scholar
63

Zhang, J., Pan, J. & Jing, W. Motivating role of type H vessels in bone regeneration. Cell Prolif. 53, e12874 (2020).
Crossref Google Scholar
64

Statello, L., Guo, C. J., Chen, L. L. & Huarte, M. Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol. 22, 96–118 (2021).
Crossref Google Scholar
65

St Laurent, G., Wahlestedt, C. & Kapranov, P. The Landscape of long noncoding RNA classification. Trends Genet. 31, 239–251 (2015).
Crossref Google Scholar
66

Chen, L. L. Linking long noncoding RNA localization and function. Trends Biochem. Sci. 41, 761–772 (2016).
Crossref Google Scholar
67

Xu, J. et al. A comprehensive overview of lncRNA annotation resources. Brief. Bioinform 18, 236–249 (2017).
Google Scholar
68

Zhao, X., Su, L., He, X., Zhao, B. & Miao, J. Long noncoding RNA CA7-4 promotes autophagy and apoptosis via sponging MIR877-3P and MIR5680 in high glucose-induced vascular endothelial cells. Autophagy 16, 70–85 (2020).
Crossref Google Scholar
69

Leisegang, M. S. et al. Long noncoding RNA MANTIS facilitates endothelial angiogenic function. Circulation 136, 65–79 (2017).
Crossref Google Scholar
70

Peng, W. X., Koirala, P. & Mo, Y. Y. LncRNA-mediated regulation of cell signaling in cancer. Oncogene 36, 5661–5667 (2017).
Crossref Google Scholar
71

Long, Y., Wang, X., Youmans, D. T. & Cech, T. R. How do lncRNAs regulate transcription? Sci. Adv. 3, eaao2110 (2017).
Crossref Google Scholar
72

Robinson, E. K., Covarrubias, S. & Carpenter, S. The how and why of lncRNA function: an innate immune perspective. Biochim Biophys. Acta Gene Regul. Mech. 1863, 194419 (2020).
Crossref Google Scholar
73

Bridges, M. C., Daulagala, A. C. & Kourtidis, A. LNCcation: lncRNA localization and function. J. Cell Biol. 220, e202009045 (2021).
Crossref Google Scholar
74

Ju, C. et al. Mesenchymal stem cell-associated lncRNA in osteogenic differentiation. Biomed. Pharmacother. 115, 108912 (2019).
Crossref Google Scholar
75

Grossi, E. et al. A lncRNA-SWI/SNF complex crosstalk controls transcriptional activation at specific promoter regions. Nat. Commun. 11, 936 (2020).
Crossref Google Scholar
76

Trembinski, D. J. et al. Aging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction. Nat. Commun. 11, 2039 (2020).
Crossref Google Scholar
77

Kwon, I. et al. Phosphorylation-regulated binding of RNA polymerase Ⅱ to fibrous polymers of low-complexity domains. Cell 155, 1049–1060 (2013).
Crossref Google Scholar
78

Singh, A. K., Kapoor, V., Thotala, D. & Hallahan, D. E. TAF15 contributes to the radiation- inducible stress response in cancer. Oncotarget 11, 2647–2659 (2020).
Crossref Google Scholar
79

Kashyap, M., Ganguly, A. K. & Bhavesh, N. S. Structural delineation of stem-loop RNA binding by human TAF15 protein. Sci. Rep. 5, 17298 (2015).
Crossref Google Scholar
80

Bonucci, A., Murrali, M. G., Banci, L. & Pierattelli, R. A combined NMR and EPR investigation on the effect of the disordered RGG regions in the structure and the activity of the RRM domain of FUS. Sci. Rep. 10, 20956 (2020).
Crossref Google Scholar
Bone Research
Volume 11,
December 2023
Article number: 27
DOI: 10.1038/s41413-023-00259-8
Cite this article:
Zhang F, Wei L, Wang L, et al. FAR591 promotes the pathogenesis and progression of SONFH by regulating Fos expression to mediate the apoptosis of bone microvascular endothelial cells. Bone Research, 2023, 11: 27. https://doi.org/10.1038/s41413-023-00259-8

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Received: 08 August 2022
Revised: 27 February 2023
Accepted: 09 March 2023
Published: 22 May 2023
© The Author(s) 2023

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