Research Abstract:
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 in T2DM by regulating osteogenic lineage allocation of vascular mesenchymal progenitors. Inflammatory redox cues initiated by TNF-alpha and osteopontin modulate the sustained activation of this arterial injury response. We now study how strategies that differentially target skeletal vs. aortic Wnt signaling differentially regulate bone formation and vascular calcification, respectively, using a murine model of diabetic vascular disease.
Selected Publications:
Cheng SL, Shao JS, Cai J, Sierra OL, Towler DA. Msx2 exerts bone anabolism via canonical Wnt signaling. J Biol Chem. 2008 283: 20505-20522.
Al-Aly Z, Shao JS, Lai CF, Huang E, Cai J, Behrmann A, Cheng SL, Towler DA. Aortic Msx2-Wnt calcification cascade is regulated by TNF-alpha-dependent signals in diabetic Ldlr-/- mice. Arterioscler Thromb Vasc Biol. 2007 27: 2589-96.
Lai CF, Seshadri V, Huang K, Shao JS, Cai J, Vattikuti R, Schumacher A, LoewyAP, Denhardt DT, Rittling SR, Towler DA. An osteopontin-NADPH oxidase signaling cascade promotes pro-matrix metalloproteinase 9 activation in aortic mesenchymal cells. Circ Res 2006 98: 1479-1489.
Shao JS, Cai J, Towler DA. Molecular mechanisms of vascular calcification. Arterioscler Thromb Vasc Biol. 2006 26: 1423-30.
Shao JS, Cheng SL, Pingsterhaus JM, Charlton-Kachigian N, Loewy AP, Towler DA. Msx2 Promotes cardiovascular calcification by activating paracrine Wnt signals. J Clin Invest 2005 115: 1210-1220.
Last Updated: 07/14/2008 |