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 arterial 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 Wnt gene expression, and activate pro-calcific Wnt signals in aortic tunica media and valves. We have identified that paracrine Wnt/Dkk signals control arterial calcification and fibrosis in T2DM by regulating osteogenic lineage allocation of diverse vascular mesenchymal progenitors. Prosclerotic inflammatory signals initiated by advanced glycation end products and TNF  -- but inhibited by the vascular smooth muscle  "osteotropic" receptors LRP6 and PTH1R-- mitigate the sustained activation of arterial injury responses including fibrosis with or without calcification. Alternative noncanonical Wnt signals provided by Wnt16, mediated by the Taz(Wwtr1)/Yap1 transcriptional relay and mitochondrial proteostasis, simultaneously preserve cardiovascular and skeletal health with diabetes and inflammaging.  We now study how strategies that differentially modulate skeletal vs. arterial Wnt16 and PTH1R signals regulate bone-vascular endocrine physiology, and evaluate the role of PTH1R-regulated plasma extracellular vesicles as  markers and mediators of cardiometabolic injury.