Secreted Phosphoprotein 1 in Lung Diseases
Abstract
1. Introduction
- SPP1-a, the full-length transcript containing all seven exons;
- SPP1-b, lacking exon 5;
- SPP1-c, lacking exon 4;
- SPP1-4, which lacks both exons 4 and 5;
- SPP1-5, which includes a retained intronic region between exons 3 and 4 that adds a novel exon and alters the translation start site. Subvariants of SPP1-5 (e.g., SPP1-5b through SPP1-5e) contain specific insertions or deletions in the novel exon. These splice variants differ in motifs for phosphorylation and transglutaminase crosslinking, contributing to isoform-specific functions in disease. Moreover, SPP1 exists in both intracellular and secreted forms and undergoes extensive post-translational modifications, including serine/threonine phosphorylation and glycosylation [2], which differentially influence its function. Exon 2 encodes the signal peptide necessary for secretion, while exons 3 through 7 contribute to its phosphorylation sites, calcium-binding domains, and receptor-binding motifs. The extracellular form of SPP1 primarily exerts its effects through interactions with integrins and CD44, regulating cellular functions such as migration, adhesion, and proliferation [3,4,5]. SPP1 contains a conserved Arg-Gly-Asp (RGD) motif, which facilitates integrin binding and is regulated by active thrombin cleavage [6]. The integrin-binding Arg-Gly-Asp (RGD) motif, located in exon 6, is essential for binding to αvβ3, αvβ5, and α8β1 integrins, and the SVVYGLR domain enables interaction with α4β1, α9β1, and α4β7 integrins. In addition to thrombin, matrix metalloproteinases (MMPs)—specifically MMP-3 and MMP-7—can also cleave SPP1 [7]. While most research has focused on the extracellular form, intracellular SPP1, located in the cytoplasm and nucleus, can act independently of receptor-mediated pathways, influencing processes such as calcium signaling, cytoskeletal organization, and apoptosis [8]. This dual localization raises important questions about how each form of SPP1 contributes to disease progression, either through extracellular signaling or intracellular regulation. The context of SPP1 expression—whether as part of a physiological adaptation or a pathological response—is also critical. In some instances, SPP1 upregulation may reflect an adaptive response to injury or inflammation, promoting tissue repair and cellular survival. Indeed, SPP1 has been shown to be a critical factor for lung development in mice [9]. However, SPP1 may contribute to disease processes such as fibrosis, immune dysregulation, or cancer metastasis. This multifaceted nature—being both protective and pathogenic—underscores the need for a nuanced understanding of SPP1’s isoform- and cell-specific functions, subcellular localization, and disease context.
2. SPP1 in Interstitial Lung Diseases
3. SPP1 in Infectious Granulomatous Lung Diseases
4. SPP1 in Lung and Pleural Malignancies
5. SPP1 in Obstructive Lung Diseases and Reactive Airway Diseases
6. SPP1 in COVID-19-Associated Lung Disease
7. Future Research
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Lung Disease | SPP1 Function/Role | ||
---|---|---|---|
Interstitial Lung Disease | Idiopathic Pulmonary Fibrosis |
| |
CTD-associated ILD |
| ||
Pneumoconiosis |
| ||
Granulomatous Lung Diseases (noninfectious) |
| ||
Infectious Granulomatous Diseases (e.g., TB) |
| ||
Lung and Pleural Malignancies |
| ||
Obstructive Lung Disease and Reactive Airway Disease | COPD |
| |
Asthma |
| ||
COVID-19-associated Lung Disease |
|
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Liu, H.; Coarfa, C.; Charania, A.N.; Larson-Casey, J.L.; Rosas, I.O.; He, C. Secreted Phosphoprotein 1 in Lung Diseases. Metabolites 2025, 15, 365. https://doi.org/10.3390/metabo15060365
Liu H, Coarfa C, Charania AN, Larson-Casey JL, Rosas IO, He C. Secreted Phosphoprotein 1 in Lung Diseases. Metabolites. 2025; 15(6):365. https://doi.org/10.3390/metabo15060365
Chicago/Turabian StyleLiu, Hongli, Cristian Coarfa, Arzoo N. Charania, Jennifer L. Larson-Casey, Ivan O. Rosas, and Chao He. 2025. "Secreted Phosphoprotein 1 in Lung Diseases" Metabolites 15, no. 6: 365. https://doi.org/10.3390/metabo15060365
APA StyleLiu, H., Coarfa, C., Charania, A. N., Larson-Casey, J. L., Rosas, I. O., & He, C. (2025). Secreted Phosphoprotein 1 in Lung Diseases. Metabolites, 15(6), 365. https://doi.org/10.3390/metabo15060365