SPARC, also known as secreted protein acidic and rich in cysteine, osteonectin, or BM-40, is a matricellular protein. It regulates cell adhesion, extracellular matrix production, growth factor activity, and the cell cycle. It modulates cell-extracellular matrix interactions due to its anti-proliferative and anti-adhesion properties. SPARC is involved in multiple pathways, such as TGF-β1 or HIF2A signaling in pulmonary arterial smooth muscle cells (PASMCs), and TLR4-mediated TBK1, IRF3, IFN-β, and STAT1 signaling in macrophages [1,2]. It is important in various biological processes and diseases, including pulmonary hypertension, aging-related inflammation, and cancer [1-3].

In the context of pulmonary hypertension, adeno-associated virus-mediated Sparc knockdown in adult mice significantly improved hemodynamic and cardiac function in PH mice, suggesting its role in the pathogenesis of human PH and chronic hypoxia-induced PH in mice, likely by affecting vascular cell function [1]. In macrophages during aging, adipocyte-specific deletion of SPARC reduced inflammation and extended health span, indicating that SPARC is an immunometabolic checkpoint of inflammation and interferon response [2].

In conclusion, SPARC plays essential roles in multiple biological processes and diseases. The gene knockout or knockdown models in mice have been crucial in revealing its role in pulmonary hypertension and aging-related inflammation, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Veith, Christine, Vartürk-Özcan, Ipek, Wujak, Magdalena, Sommer, Natascha, Weissmann, Norbert. 2022. SPARC, a Novel Regulator of Vascular Cell Function in Pulmonary Hypertension. In Circulation, 145, 916-933. doi:10.1161/CIRCULATIONAHA.121.057001. https://pubmed.ncbi.nlm.nih.gov/35175782/

2. Ryu, Seungjin, Sidorov, Sviatoslav, Ravussin, Eric, Wang, Andrew, Dixit, Vishwa Deep. 2022. The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging. In Immunity, 55, 1609-1626.e7. doi:10.1016/j.immuni.2022.07.007. https://pubmed.ncbi.nlm.nih.gov/35963236/