New Therapeutics Targeting Arterial Media Calcification: Friend or Foe for Bone Mineralization?

Abstract

The presence of arterial media calcification, a highly complex and multifactorial disease, puts patients at high risk for developing serious cardiovascular consequences and mortality. Despite the numerous insights into the mechanisms underlying this pathological mineralization process, there is still a lack of effective treatment therapies interfering with the calcification process in the vessel wall. Current anti-calcifying therapeutics may induce detrimental side effects at the level of the bone, as arterial media calcification is regulated in a molecular and cellular similar way as physiological bone mineralization. This especially is a complication in patients with chronic kidney disease and diabetes, who are the prime targets of this pathology, as they already suffer from a disturbed mineral and bone metabolism. This review outlines recent treatment strategies tackling arterial calcification, underlining their potential to influence the bone mineralization process, including targeting vascular cell transdifferentiation, calcification inhibitors and stimulators, vascular smooth muscle cell (VSMC) death and oxidative stress: are they a friend or foe? Furthermore, this review highlights nutritional additives and a targeted, local approach as alternative strategies to combat arterial media calcification. Paving a way for the development of effective and more precise therapeutic approaches without inducing osseous side effects is crucial for this highly prevalent and mortal disease.

Keywords: arterial calcification; bone metabolism; cell death; chronic kidney disease; nutrition; oxidative stress; phenotypic transition; vascular therapy.

Figure 1

Targeting vascular smooth muscle cell (VSMC) death and oxidative stress-related processes as a possible way to tackle arterial media calcification and its effect on bone mineralization. (A) Apoptosis, a caspase-dependent type of cell death, contributes to the development of arterial media calcification. Apoptotic bodies act as a nucleation site for the deposition of calcium-phosphate crystals. The caspase inhibitor ZVAD.fmk has shown its efficiency in inhibiting arterial calcification but may cause detrimental effects on bone metabolism as caspases play an important role in physiological bone mineralization as well. (B) Oxidative stress, a central process in the onset of arterial calcification, either results in the generation of reactive oxygen species (ROS) which in turn drives the onset of apoptosis and ferroptosis, or the upregulation of poly(ADP-ribose) polymerase-1 (PARP-1) which stimulates the osteogenic transdifferentiation of VSMCs. Antioxidants and PARP inhibitors (i.e., minocycline) encounter arterial calcification but respectively enhance or disturb physiological bone mineralization. (C) A possible role of lipid peroxidation and ferroptosis (i.e., an iron-mediated type of regulated cell death) in arterial media calcification. Both mechanisms might be targeted without causing side-effects on the bone metabolism as metformin, vitamin E and ferrostatin-1 (Fer-1), which are therapeutics shown to inhibit ferroptotic events, show stimulatory effects on bone formation. Furthermore, selenium administration is known to inhibit VSMC calcification but also is an important co-factor of glutathione peroxidase 4 (Gpx4), an important regulator in ferroptosis. (D) The intravenous (IV) injections of iron to CKD patients on dialysis and inflammatory states cause a hepcidin upregulation, which in turn downgrades ferroportin (i.e., an important iron exporter) and causes intracellular iron sequestration. On one hand, this can induce lipid peroxidation and ferroptosis, and on the other hand, iron overload is known to favor a disturbed bone metabolism. Upward arrow indicates upregulation while downward arrow indicates downregulation.