Spp1, also known as osteopontin (OPN), is a multifunctional secreted phosphorylated glycoprotein. It is expressed in several cell types such as osteoblasts, fibroblasts, macrophages, and is involved in various biological processes. Spp1-related pathways include those regulating inflammation, fibrosis, and cell-cell communication, playing an overall significant role in health and disease [4]. Genetic models, like KO and CKO mouse models, have been crucial in studying its functions.

In non-alcoholic steatohepatitis (NASH), conditional knockout of Spp1 in myeloid cells (Spp1ΔMye) worsened NASH, while conditional knockin in myeloid cells (Spp1KI Mye) or hepatic macrophages (Spp1KI LvMF) conferred protection. The protection was mediated by upregulating oncostatin-M (OSM), which increased arginase-2 (ARG2) through STAT3 signaling, enhancing fatty acid oxidation in hepatocytes [1]. In idiopathic pulmonary fibrosis, SPP1hi macrophages showed highly upregulated SPP1 and MERTK expression, and their proliferation was increased in fibrotic lungs compared to normal lungs, contributing to lung fibrosis [2]. In fibrosis of the heart and kidney, platelets drive the differentiation of profibrotic Spp1 macrophages via CXCL4, and loss of Cxcl4 abrogates their differentiation and ameliorates fibrosis [3].

In conclusion, Spp1 is involved in multiple disease-related processes. Model-based research, especially through Spp1 KO/CKO mouse models, has revealed its significant role in NASH, pulmonary fibrosis, and organ-specific fibrosis. These findings provide insights into potential therapeutic strategies targeting Spp1-related pathways in these disease areas.

References:

1. Han, Hui, Ge, Xiaodong, Komakula, Sai Santosh Babu, Guzman, Grace, Nieto, Natalia. 2023. Macrophage-derived Osteopontin (SPP1) Protects From Nonalcoholic Steatohepatitis. In Gastroenterology, 165, 201-217. doi:10.1053/j.gastro.2023.03.228. https://pubmed.ncbi.nlm.nih.gov/37028770/

2. Morse, Christina, Tabib, Tracy, Sembrat, John, Rojas, Mauricio, Lafyatis, Robert. 2019. Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis. In The European respiratory journal, 54, . doi:10.1183/13993003.02441-2018. https://pubmed.ncbi.nlm.nih.gov/31221805/

3. Hoeft, Konrad, Schaefer, Gideon J L, Kim, Hyojin, Hayat, Sikander, Kramann, Rafael. 2023. Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner. In Cell reports, 42, 112131. doi:10.1016/j.celrep.2023.112131. https://pubmed.ncbi.nlm.nih.gov/36807143/

4. Matsubara, Eri, Yano, Hiromu, Pan, Cheng, Kurotaki, Daisuke, Suzuki, Makoto. 2023. The Significance of SPP1 in Lung Cancers and Its Impact as a Marker for Protumor Tumor-Associated Macrophages. In Cancers, 15, . doi:10.3390/cancers15082250. https://pubmed.ncbi.nlm.nih.gov/37190178/