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Dorsomorphin homologue 1, a highly selective small-molecule bone morphogenetic protein inhibitor, suppresses medial
Tonghui Lin1, Xue-Lin Wang1, Sara L Zettervall1
1Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.
Insights
Dorsomorphin homologue 1 (DMH1), a bone morphogenetic protein inhibitor, effectively reduced medial artery calcification in human cells and aortic tissues. This suggests DMH1 may offer a therapeutic strategy for vascular calcification.
Area of Science:
- Vascular Biology
- Biochemistry
- Pharmacology
Background:
- Medial artery calcification is linked to diabetes, CKD, aging, and increased patient mortality.
- Bone morphogenetic proteins (BMPs) are implicated in vascular calcification initiation and progression.
- Investigating selective BMP inhibitors like DMH1 is crucial for understanding and potentially treating vascular calcification.
Purpose of the Study:
- To evaluate the efficacy of dorsomorphin homologue 1 (DMH1), a selective BMP inhibitor, in attenuating medial artery calcification.
- To assess DMH1's effects on vascular smooth muscle cells (SMCs) and in an organ culture model of medial calcification.
Main Methods:
- Human aortic SMCs cultured with inorganic phosphate (Pi) +/- DMH1.
- Aortic organ culture model used to assess medial calcification.
- Alizarin red S staining, calcium assays, Western blot, and qPCR analyzed calcification and marker expression.
Main Results:
- DMH1 significantly reduced Pi-induced calcium deposition in human SMCs and antagonized BMP2-induced calcification.
- DMH1 inhibited osteogenic markers (osterix, alkaline phosphatase) and upregulated SMC markers (SM-MHC, SM22α).
- DMH1 suppressed BMP/Smad1/5/8 signaling and reduced medial calcification in aortic ring organ cultures.
Conclusions:
- The BMP inhibitor DMH1 effectively reduces vascular SMC and arterial calcification induced by elevated phosphate.
- DMH1 demonstrates potential as a therapeutic agent for medial artery calcification in at-risk patient populations.
Background:
Medial artery calcification develops in diabetes, chronic kidney disease, and as part of the aging process. It is associated with increased morbidity and mortality in vascular patients. Bone morphogenetic proteins (BMPs) have previously been implicated in the initiation and progression of vascular calcification. We thus evaluated whether dorsomorphin homologue 1 (DMH1), a highly selective BMP inhibitor, could attenuate vascular calcification in vitro and in an organ culture model of medial calcification.
Methods:
Confluent human aortic smooth muscle cells (SMCs) were cultured in calcification medium containing 3.0 mM inorganic phosphate (Pi) for 7 days with or without DMH1. Medial calcification was assessed using an aortic organ culture model. Calcification was visualized by alizarin red S staining, and calcium concentration was assessed by an o-cresolphthalein complexone calcium assay. Osteogenic cell and vascular SMC markers were determined by Western blot, quantitative reverse transcription polymerase chain reaction, and immunohistochemical staining.
Results:
DMH1 reduced Pi-induced calcium deposition in human SMCs. It also antagonized human recombinant BMP2-induced calcium accumulation. Western blot further revealed that DMH1 was able to block Pi-mediated upregulation of the osteoblast markers osterix and alkaline phosphatase and downregulation of the SMC markers smooth muscle myosin heavy chain and SM22α as well as p-Smad1/5/8, suggesting that DMH1 may regulate SMC osteogenic differentiation through the BMP/Smad1/5/8 signaling pathway. Finally, using an ex vivo aortic ring organ culture model, we observed that DMH1 reduces Pi-induced aortic medial calcification.
Conclusions:
The selective BMP inhibitor DMH1 can inhibit calcium accumulation in vascular SMCs and arterial segments exposed to elevated phosphate levels. Such small molecules may have clinical utility in reducing medial artery calcification in our population of vascular patients.
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