ArticleHuman molecular genetics2019
Spp1 (osteopontin) promotes TGFβ processing in fibroblasts of dystrophin-deficient muscles through matrix metalloproteinases.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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Who cites it
73 citing papers in PubMed, 95 citations in OpenAlex.
- TGF-β signalling drives chemotaxis of human induced pluripotent stem cell-derived cardiomyocytes in response to MI stimulus.Basic research in cardiology · 2026Article
- A placental and fetal liver TGFβ signaling axis drives fetal immunosuppression in maternal obesity.iScience · 2026Article
- Targeting CCR1 Remodels the Tumor Microenvironment and Relieves Immunosuppression in Pancreatic Cancer.Cancer immunology research · 2026Article
- Hepatokines lipocalin 2 and osteopontin drive muscle atrophy in MASH.Molecular metabolism · 2026Article
- Macrophage regulation of extracellular matrix remodeling in aging skeletal muscle.Ageing research reviews · 2026Review
- Single-Cell dissection of fibrodysplasia ossificans progressiva identifies SPP1 as a mediator of macrophage-fibroadipogenic progenitors crosstalk.Cellular and molecular life sciences : CMLS · 2026Article
- Collagen-producing eye cell atlas reveals distinct fibroblast fates in early injury vs. fibrotic subretinal disease.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Identification of potential therapeutic targetiScience · 2026Article
- Macrophage and fibro-adipogenic progenitor communication in skeletal muscle regeneration: tissue homeostasis and pathogenic remodeling.Journal of leukocyte biology · 2026Review
- Single-cell transcriptomics highlights macrophage-driven regulation of EndMT and repair in injured muscle.Communications biology · 2026Article
- Epidermal PPARγ Signaling as a Suppressor of Toll-like Receptor-Mediated Inflammation and Fibrosis: Relevance to Cutaneous Squamous Cell Carcinoma.International journal of molecular sciences · 2026Article
- Fibroblast-like Synoviocytes as Key Regulators of Homeostasis and Inflammation in the Joint Microenvironment of Inflammatory Arthritis.Biomedicines · 2026Article
- Reprogrammed Fibrotic Niche Fuels Lung Cancer Initiation and Reciprocal Remodeling.International journal of biological sciences · 2026Review
- Macrophage plasticity and metabolic control in muscle repair and disease.Frontiers in immunology · 2026Review
- From support to homeostatic licensing: the bidirectional fibroblast-macrophage circuit and its central role in tissue homeostasis and fibrosis.Frontiers in immunology · 2026Review
- Degradation of Elastic Fiber Triggers Lacrimal Gland Dysfunction in Marfan Syndrome Mice.Investigative ophthalmology & visual science · 2025Article
- Repurposed Drugs for Heterotopic Ossification Management: Revitalizing Therapeutic Strategies.Pharmaceuticals (Basel, Switzerland) · 2025Article
- The Landscape of SPP1Immunology · 2025Review
- Collagen in pituitary adenomas: A comprehensive review of biological roles and clinical implications.Journal of clinical & translational endocrinology · 2025Review
- The functional role of the extracellular matrix in inflammatory bowel disease associated gut fibrosis.Matrix biology : journal of the International Society for Matrix Biology · 2025Review
13 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
Abstract
Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin. Prior work has shown that DMD progression can vary, depending on the genetic makeup of the patient. Several modifier alleles have been identified including LTBP4 and SPP1. We previously showed that Spp1 exacerbates the DMD phenotype in the mdx mouse model by promoting fibrosis and by skewing macrophage polarization. Here, we studied the mechanisms involved in Spp1's promotion of fibrosis by using both isolated fibroblasts and genetically modified mice. We found that Spp1 upregulates collagen expression in mdx fibroblasts by enhancing TGFβ signaling. Spp1's effects on TGFβ signaling are through induction of MMP9 expression. MMP9 is a protease that can release active TGFβ ligand from its latent complex. In support for activation of this pathway in our model, we showed that treatment of mdx fibroblasts with MMP9 inhibitor led to accumulation of the TGFβ latent complex, decreased levels of active TGFβ and reduced collagen expression. Correspondingly, we found reduced active TGFβ in Spp1-/-mdxB10 and Mmp9-/-mdxB10 muscles in vivo. Taken together with previous observations of reduced fibrosis in both models, these data suggest that Spp1 acts upstream of TGFβ to promote fibrosis in mdx muscles. We found that in the context of constitutively upregulated TGFβ signaling (such as in the mdxD2 model), ablation of Spp1 has very little effect on fibrosis. Finally, we performed proof-of-concept studies showing that postnatal pharmacological inhibition of Spp1 reduces fibrosis and improves muscle function in mdx mice.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.