Osteopontin and Lung Scarring in Scleroderma

OSTEOPONTIN (OPN), a protein known to function as an immune system modulator and play a role in tissue regeneration, may be responsible for driving lung scarring in patients with systemic sclerosis (SSc). This form of scleroderma, characterised by the inflammation and fibrosis of a range of organs, had a prevalence of approximately 307 per million in the UK in 2018. Despite this, there is neither a clear pathogenesis nor cure at present.

For this reason, Dr Dinesh Khanna, director of Michigan Medicine’s Scleroderma Programme, University of Michigan, Ann Arbor, Michigan, USA, identified specific biomarkers that could help identify patients at higher risk of this progressive disease. When discussing the relevance of the research, Dr Khanna commented: “We have accepted the challenge of trying to help patients the best we can, by continuing a search for a treatment or cure.”

The study identified a glyco-phosphoprotein, OPN, which is purportedly responsible for triggering lung scarring. Bulk RNA-sequencing (RNA-seq) demonstrated that SPP1 transcripts, which encode for OPN, were significantly upregulated in explanted lung tissue from SSc interstitial lung disease (ILD) patients relative to non-diseased control samples. Although numerous cell types have been implicated in the biosynthesis of OPN, a subsequent methodological approach was employed to further define the cellular context of production in SSc lung tissue. In this instance, cell suspensions derived from explanted lung tissue were analysed via single-cell RNA-seq. Over 29,000 cells in total, isolated from three SSC-ILD patient lungs, were sequenced, batch-effect corrected, aligned, and clustered. Canonical markers of known cell types enriched in each cluster were then used for annotation. Even though an SPP1 signal was detectable in several cell types, the dominant signal was primarily attributable to a cluster labelled as macrophages (identified via their expression of CD68, MARCO, and MSR1 marker genes).

When summarising the research findings, Dr Thiru Ramalingham, one of the study’s co-authors, stated: “When the macrophage is activated by immune complexes, we discovered that it secretes an abundance of a protein called OPN – previously implicated in fibrosis.” It was further concluded that OPN levels at a given time were prognostic for future deterioration of lung function. However, the observed prognostic effects arose from post hoc exploratory analyses using research-grade assessments. Additional validation using clinical-grade assays and prespecified inspection plans are therefore necessary to validate these findings.