Matrix Gla Protein is a novel regulator of TGFβ-dependent fibroblast activation and kidney fibrosis.

Kidney fibrosis is the pathologic hallmark of chronic kidney disease (CKD) and is driven by fibroblast-to-myofibroblast transformation (FMT), excessive extracellular matrix accumulation, and persistent activation of transforming growth factor-β (TGFβ) signaling. Although TGFβ is a central mediator of fibrosis, its pleiotropic physiological functions have limited the development of direct anti-fibrotic therapies, highlighting the need to identify context-specific regulators of this pathway. Matrix Gla Protein (MGP) is a vitamin K-dependent extracellular protein best known for inhibiting vascular calcification; however, its role in kidney fibrosis remains unknown. Here, we demonstrate that MGP expression is markedly upregulated in fibroblasts from fibrotic kidneys in mouse models of chronic kidney injury and in human CKD samples. Using inducible global and fibroblast-specific Mgp knockout mice, we show that Mgp deficiency attenuates renal fibrosis, suppresses fibroblast activation, and preserves kidney function following folic acid nephropathy and unilateral ureteral obstruction. Mechanistically, MGP promotes FMT and amplifies TGFβ receptor/Smad3 signaling, whereas genetic or molecular inhibition of MGP blunts TGFβ-driven fibroblast activation both in vivo and in vitro. We further identify phosphorylation and γ-carboxylation as essential post-translational modifications required for the profibrotic activity of MGP. In addition, MGP interacts with bone morphogenetic protein-2 (BMP-2), reduces BMP-2 protein abundance, and counteracts BMP-2-mediated suppression of TGFβ signaling, thereby enhancing profibrotic responses. Collectively, these findings identify MGP as a previously unrecognized regulator of TGFβ-dependent fibroblast activation and kidney fibrosis, supporting MGP as a potential fibroblast-associated target for future strategies aimed at limiting CKD progression.