Myeloid-derived growth factor (Mydgf), a paracrine protein secreted by bone marrow-derived monocytes and macrophages, plays crucial roles in multiple biological processes. It has been associated with pathways like c-Myc/FoxM1, MAP4K4/Akt-1/FoxO3a, MAP4K4/NF-κB, PIM1/SERCA2a, PKCβ-NF-κB, MAPK1/3-STAT3, and Akt/BAD, and is important for tissue repair, metabolism regulation, and homeostasis maintenance. Genetic mouse models, such as Mydgf knockout (Mydgf-KO) mice, are valuable for studying its functions [1-7].

In Mydgf-KO mice, neonatal heart regeneration and injury-induced cardiomyocyte proliferation were impeded, indicating Mydgf's role in heart regeneration by activating the c-Myc/FoxM1 pathway [1]. In atherosclerosis studies, monocyte/macrophage-targeted MYDGF-null mice on an Ldlr-/-background showed aggravated endothelial LDL transcytosis and exacerbated atherosclerosis, revealing that inflammatory cell-derived MYDGF inhibits LDL transcytosis [2]. Myeloid cell-specific MYDGF deficiency in mice exacerbated vascular inflammation, adhesion responses, endothelial injury, and atherosclerosis, while restoration had the opposite effects, suggesting MYDGF's role in protecting against endothelial injury and atherosclerosis through MAP4K4/NF-κB signaling [3]. Mydgf-/-mice developed more severe left ventricular hypertrophy and contractile dysfunction during pressure overload, highlighting MYDGF's protective role against pressure-overload-induced heart failure by preserving SERCA2a expression [4]. Tubule-specific deletion of Mydgf in mice exacerbated kidney injury in chronic kidney disease (CKD), indicating that renal tubular MYDGF may be an effective therapeutic strategy for CKD by maintaining mitochondrial homeostasis [5]. Myeloid cell-specific MYDGF deficiency decreased bone mass and strength in mice, showing MYDGF's positive regulation of bone homeostasis [6]. MYDGF deficiency in diabetic kidney disease (DKD) mouse models caused more severe podocyte and glomerular injury, while replenishment alleviated these injuries, suggesting MYDGF's potential as a treatment strategy for DKD [7].

In conclusion, Mydgf is essential for various biological functions including heart regeneration, endothelial protection, prevention of heart failure, kidney function maintenance, and bone homeostasis. The use of Mydgf KO mouse models has significantly contributed to understanding its role in these disease areas, providing potential therapeutic targets for heart failure, atherosclerosis, CKD, osteoporosis, and DKD.