Dwight A. Towler, MD, PhD
Year elected: 2004
Current membership category: Senior
J.D. and Maggie E. Wilson Distinguished Chair in Biomedical Science, Professor of MedicineUniversity of Texas Southwestern Medical Center
Department of Internal Medicine - Endocrine Division
5323 Harry Hines Blvd
Dallas, TX 75390-8857
United States of America
Phone: (214) - 648-2982
Tremendous unmet needs exist in musculoskeletal medicine. Osteoporosis and osteoarthritis are recognized as common and clinically important, but other serious skeletal disorders also afflict our society. In the setting of type 2 diabetes mellitus (T2DM), lower-extremity musculoskeletal disease is prevalent, costly, and exceedingly difficult to manage, with fracture, arthropathy, ischemia, ulcer, infection, and amputation commonly confronting patients and clinicians. Aortofemoral medial artery calcification is a strong predictor of risk for lower extremity amputation in patients with T2DM. While not occluding the lumen, mural elastinolysis and medial calcification compromise arterial elasticity -- a material property necessary for Windkessel physiology that ensures normal tissue perfusion throughout the cardiac cycle. During aortic calcification, the Msx2-Wnt signaling cascade that controls orthotopic craniofacial bone formation is activated ectopically in the aortic valve and vessel wall. Diabetes and dyslipidemia induce expression of Msx2 in arterial myofibroblasts, upregulate aortic Wnt3a and Wnt7a gene expression, and activate pro-calcific canonical Wnt signaling in the valve and tunica media. By studying Msx2 actions, we have identified that paracrine Wnt/Dkk signals control arterial calcification and fibrosis in T2DM by regulating osteogenic lineage allocation of vascular mesenchymal progenitors. Prosclerotic inflammatory Wnt signals initiated by TNF-alpha and osteopontin -- but inhibited by vascular LRP6 and PTH1R -- modulate the sustained activation of this arterial injury response. Intracellular protein arginine methylation / demethylation has recently emerged as a novel feature of the Wnt/LRP6 regulatory relay. We now study how strategies that differentially modulate skeletal vs. arterial Wnt signaling can preserve bone homeostasis and cardiovascular health in diabetes and uremia.
University of Texas Southwestern Medical Center (Primary)
Beth Levine, MD is the representative at this institution.