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Barkas, G.I.; Kotsiou, O.S. Mechanisms and Physiological Functions of Osteopontin. Encyclopedia. Available online: https://encyclopedia.pub/entry/48593 (accessed on 23 June 2024).
Barkas GI, Kotsiou OS. Mechanisms and Physiological Functions of Osteopontin. Encyclopedia. Available at: https://encyclopedia.pub/entry/48593. Accessed June 23, 2024.
Barkas, Georgios I, Ourania S. Kotsiou. "Mechanisms and Physiological Functions of Osteopontin" Encyclopedia, https://encyclopedia.pub/entry/48593 (accessed June 23, 2024).
Barkas, G.I., & Kotsiou, O.S. (2023, August 29). Mechanisms and Physiological Functions of Osteopontin. In Encyclopedia. https://encyclopedia.pub/entry/48593
Barkas, Georgios I and Ourania S. Kotsiou. "Mechanisms and Physiological Functions of Osteopontin." Encyclopedia. Web. 29 August, 2023.
Mechanisms and Physiological Functions of Osteopontin
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The biological functions of osteopontin (OPN) are diverse and specific to physiological and pathophysiological conditions implicated in inflammation, biomineralization, cardiovascular diseases, cellular viability, cancer, diabetes, and renal stone disease. OPN influences the immune system and is a chemo-attractive protein correlated with respiratory disease severity. There is evidence that OPN can advance the disease stage associated with its fibrotic, inflammatory, and immune functions.

respiratory disease osteopontin inflammation

1. Introduction

Osteopontin (OPN) or secreted phosphoprotein 1 (SPP1) is a member of the SIBLING small integrin-binding ligand, N-linked glycoprotein (SIBLING) family of proteins, which map to human chromosome 4 [1(BMGC1) (BMGC2)]. OPN is a multifunctional glycoprotein and is found in numerous tissues of the body, such as saliva, bile, the brain, bone marrow, endothelial cells, smooth muscle cells, and pancreatic ducts. In salivary and sudoriferous glands, it is also secreted into body fluids by epithelial cells, for example, airway epithelial cells [1][2][3].
OPN presents different post-translational modifications [4][5]. It plays important roles in inflammation, biomineralization, cardiovascular diseases, cellular viability, cancer, diabetes, and renal stone disease through various pathophysiological mechanisms [6].
In biomineralization, OPN acts as an important communication mediator between osteoblasts and osteoclasts while playing a crucial role in the latter [6]. OPN acts as a conductor by playing a pivotal role in secretion levels of interleukin (IL)-10, (IL-1), (IL-3), interferon-γ (IFN-γ), integrin αvB3, and nuclear factor kappa B (NF-kB) by regulating osteoclast function and affecting CD44 receptors.
OPN is known to be a chemical attractant for macrophages and T cells, and research has been conducted to investigate its role in inflammation [2][6][7]. T cells secrete OPN when activated, affecting, particularly macrophages and causing them to migrate to sites of inflammation, therefore leading to higher levels of the protein in the serum of patients with systemic or chronic inflammation [7][8].
Moreover, OPN is a key cytokine in wound repair, serving as a chemotactic molecule to recruit inflammatory cells to the site of injury, promoting wound healing [8]. OPN communicates with cells via integrins and CD44, which involves an intracellular interaction where OPN, through a conserved region that separates both the integrin and CD44 binding domains, possesses distinct signaling functions that can link it to various forms of metastasis [9].
The biological functions of OPN are diverse and specific to a spectrum of physiological and pathophysiological conditions of the respiratory system [9][10]. OPN is constitutively expressed in the airways during healthy conditions. Evidence shows it is implicated in chronic inflammation associated with infection and regulates host immunity. High levels of OPN can be detected in sputum during states of disease characterized by prolonged airway inflammation, i.e., chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and asthma [11]. OPN is implicated as being harmful in the case of systemic inflammation [12]. However, studies have demonstrated some beneficial roles for the protein, including protection against lung injury [11] and against cardiac ischemia-reperfusion injury [13]. Moreover, studies reported that it regulates cancer development. More specifically, in non-small cell lung cancers (NSCLCs), OPN induces vascular endothelial growth factor (VEGF) expression and facilitates disease progression [10].

2. Mechanisms and Physiological Functions of Osteopontin

OPN is an acidic arginine–glycine–aspartate-containing adhesive glycoprotein that plays a role as an intrinsic component of the immune system [9]. OPN is rich in aspartic acid and consists of 300 amino acids [1]. OPN has two terminal zones, including the N-terminal and C-terminal, which bind two heparin molecules and CD44 variants, whereas the N-terminal includes integrin receptor binding zones [13]. The post-translational modifications (PTMs) of OPN, such as glycosylation and phosphorylation, significantly affect its structure and biological properties. For example, a reduction in sialylation may prevent OPN from binding to cell surface receptors [5].
OPN is important in tissue repair while also being associated with cellular regeneration. Moreover, OPN is involved in the proliferation of vascular smooth muscle cells and glomerular mesangial cells induced by hypoxia [3]. OPN expression is linked with fibrosis and scarring of the tissue, with upregulation of the protein found in animal models of renal disease.
OPN expression has been highly associated with numerous respiratory diseases, with high protein levels found in the airways and tissues of affected lungs and upregulation being present in more severe disease cases [14].
Many factors influence OPN release via various signal pathways, including protein kinase C (PKC) on specific cell types. PKC, for example, inhibits OPN release in Src−/− fibroblasts stimulated by epidermal growth factor. Furthermore, increased OPN released in response to injury and illness is linked to cytokines [3].
OPN is a cytokine with diverse roles in tissue remodeling, fibrosis, immunomodulation, inflammation, and tumor metastasis [15]. Patients with OPN deficits have been reported to be protected from airway remodeling and hyperresponsiveness [15][16][17]. Furthermore, OPN can polymerize with itself or other extracellular matrix proteins, including fibronectin, via the catalytic action of tissue transglutaminase 2 (TGM2) [14].
Recent in vitro and animal investigations reveal OPN polymerization and support the idea that OPN causes neutrophils to gain chemotactic activity via its interaction with α9β1 integrin [14], providing insight into OPN’s polymeric function in human airways.
Moreover, a significant association between polymeric OPN and the concentration of alveolar macrophages in bronchoalveolar lavage (BAL) fluid was found, which suggests a chemotactic role of polymeric OPN for alveolar macrophages in the airways. This is consistent with studies supporting OPN’s role as a chemo-attractant of inflammatory cells such as macrophages [14][15].
OPN has been identified as an asthma biomarker, usually associated with the neutrophil asthma phenotype and indicating disease severity [18].
OPN plays a crucial role in the context of the airways. It exhibits high expression within the airways and affected lung tissues, particularly in more severe respiratory conditions. OPN is involved in processes such as tissue remodeling, fibrosis, immune modulation, and inflammation. It can form polymers and interact with other proteins in the extracellular matrix, resulting in chemotactic activity that attracts neutrophils and inflammatory cells to the airways. Moreover, OPN has been identified as a valuable biomarker for asthma, specifically associated with the phenotype characterized by neutrophilic inflammation, serving as an indicator of disease severity. OPN contributes to eosinophilic airway inflammation.
Moreover, OPN can destroy the lung parenchyma through its neutrophil influx and fibrotic mechanisms, linking OPN to at least one of the two major chronic obstructive pulmonary disease phenotypes. Respiratory diseases that involve irreversible lung scarring, such as idiopathic pulmonary disease, are linked to OPN, with protein levels being overexpressed in individuals with severe or advanced stages of the disorders and considerably lower levels in those with less severe symptoms. OPN plays a significant role in lung cancer progression and metastasis. It is also implicated in the pathogenesis of pulmonary hypertension, coronavirus disease 2019, and granuloma generation.
OPN influences the immune system and is a chemo-attractive protein correlated with respiratory disease severity. There is evidence that OPN can advance the disease stage associated with its fibrotic, inflammatory, and immune functions. In other words, it seems that OPN plays a crucial role in respiratory disease and health.

References

  1. Si, J.; Wang, C.; Zhang, D.; Wang, B.; Hou, W.; Zhou, Y. Osteopontin in Bone Metabolism and Bone Diseases. Experiment 2020, 26, e919159-1–e919159-9.
  2. Chen, Q.; Shou, P.; Zhang, L.; Xu, C.; Zheng, C.; Han, Y.; Li, W.; Huang, Y.; Zhang, X.; Shao, C.; et al. An Osteopontin-Integrin Interaction Plays a Critical Role in Directing Adipogenesis and Osteogenesis by Mesenchymal Stem Cells. Stem Cells 2014, 32, 327–337.
  3. Bastos, A.C.S.d.F.; Gomes, A.V.P.; Silva, G.R.; Emerenciano, M.; Ferreira, L.B.; Gimba, E.R.P. The Intracellular and Secreted Sides of Osteopontin and Their Putative Physiopathological Roles. Int. J. Mol. Sci. 2023, 24, 2942.
  4. Yim, A.; Smith, C.; Brown, A.M. Osteopontin/secreted phosphoprotein-1 harnesses glial-, immune-, and neuronal cell ligand-receptor interactions to sense and regulate acute and chronic neuroinflammation. Immunol. Rev. 2022, 311, 224–233.
  5. Li, H.; Shen, H.; Yan, G.; Zhang, Y.; Liu, M.; Fang, P.; Yu, H.; Yang, P. Site-specific structural characterization of O-glycosylation and identification of phosphorylation sites of recombinant osteopontin. Biochim. Biophys. Acta Proteins Proteom. 2015, 1854, 581–591.
  6. Içer, M.A.; Gezmen-Karadag, M. The multiple functions and mechanisms of osteopontin. Clin. Biochem. 2018, 59, 17–24.
  7. Lamort, A.-S.; Giopanou, I.; Psallidas, I.; Stathopoulos, G.T. Osteopontin as a Link between Inflammation and Cancer: The Thorax in the Spotlight. Cells 2019, 8, 815.
  8. Castello, L.M.; Raineri, D.; Salmi, L.; Clemente, N.; Vaschetto, R.; Quaglia, M.; Garzaro, M.; Gentilli, S.; Navalesi, P.; Cantaluppi, V.; et al. Osteopontin at the crossroads of inflammation and tumor progression. Mediat. Inflamm. 2017, 2017, 1–22.
  9. Zhao, H.; Chen, Q.; Alam, A.; Cui, J.; Suen, K.C.; Soo, A.P.; Eguchi, S.; Gu, J.; Ma, D. The role of osteopontin in the progression of solid organ tumour. Cell Death Dis. 2018, 9, 356.
  10. Lin, Q.; Guo, L.; Lin, G.; Chen, Z.; Chen, T.; Lin, J.; Zhang, B.; Gu, X. Clinical and prognostic significance of OPN and VEGF expression in patients with non-small-cell lung cancer. Cancer Epidemiol. 2015, 39, 539–544.
  11. Kasetty, G.; Papareddy, P.; Bhongir, R.K.V.; Ali, M.N.; Mori, M.; Wygrecka, M.; Erjefält, J.S.; Hultgårdh-Nilsson, A.; Palmberg, L.; Herwald, H.; et al. Osteopontin protects against lung injury caused by extracellular histones. Mucosal Immunol. 2019, 12, 39–50.
  12. Hirano, Y.; Aziz, M.; Yang, W.-L.; Ochani, M.; Wang, P. Neutralization of Osteopontin Ameliorates Acute Lung Injury Induced by Intestinal Ischemia-Reperfusion. Shock 2016, 46, 431–438.
  13. Wang, Y.; Chen, B.; Shen, D.; Xue, S. Osteopontin protects against cardiac ischemia-reperfusion injury through late preconditioning. Heart Vessel. 2009, 24, 116–123.
  14. Nomiyama, T.; Perez-Tilve, D.; Ogawa, D.; Gizard, F.; Zhao, Y.; Heywood, E.B.; Jones, K.L.; Kawamori, R.; Cassis, L.A.; Tschöp, M.H.; et al. Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. J. Clin. Investig. 2007, 117, 2877–2888.
  15. Jiang, Y.-J.; Chao, C.-C.; Chang, A.-C.; Chen, P.-C.; Cheng, F.-J.; Liu, J.-F.; Liu, P.-I.; Huang, C.-L.; Guo, J.-H.; Huang, W.-C.; et al. Cigarette smoke-promoted increases in osteopontin expression attract mesenchymal stem cell recruitment and facilitate lung cancer metastasis. J. Adv. Res. 2022, 41, 77–87.
  16. Chen, L.; Huan, X.; Xiao, G.-H.; Yu, W.-H.; Li, T.-F.; Gao, X.-D.; Zhang, Y.-C. Osteopontin and its downstream carcinogenic molecules: Regulatory mechanisms and prognostic value in cancer progression. Neoplasma 2022, 69, 1253–1269.
  17. Khamissi, F.Z.; Ning, L.; Kefaloyianni, E.; Dun, H.; Arthanarisami, A.; Keller, A.; Atkinson, J.J.; Li, W.; Wong, B.; Dietmann, S.; et al. Identification of kidney injury released circulating osteopontin as causal agent of respiratory failure. Sci. Adv. 2022, 8, eabm5900.
  18. Kruger, T.E.; Miller, A.H.; Godwin, A.K.; Wang, J. Bone sialoprotein and osteopontin in bone metastasis of osteotropic cancers. Crit. Rev. Oncol. 2013, 89, 330–341.
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