Calcifying circulating cells: an uncharted area in the setting of vascular calcification in CKD patients

Abstract

Vascular calcification, occurring during late-stage vascular and valvular disease, is highly associated with chronic kidney disease-mineral and bone disorders (CKD-MBD), representing a major risk factor for cardiovascular morbidity and mortality. The hallmark of vascular calcification, which involves both media and intima, is represented by the activation of cells committed to an osteogenic programme. Several studies have analysed the role of circulating calcifying cells (CCCs) in vascular calcification. CCCs are bone marrow (BM)-derived cells with an osteogenic phenotype, participating in intima calcification processes and defined by osteocalcin and bone alkaline phosphatase expression. The identification of CCCs in diabetes and atherosclerosis is the most recent, intriguing and yet uncharted chapter in the scenario of the bone-vascular axis. Whether osteogenic shift occurs in the BM, the bloodstream or both, is not known, and also the factors promoting CCC formation have not been identified. However, it is possible to recognize a common pathogenic commitment of inflammation in atherosclerosis and diabetes, in which metabolic control may also have a role. Currently available studies in patients without CKD did not find an association of CCCs with markers of bone metabolism. Preliminary data on CKD patients indicate an implication of mineral bone disease in vascular calcification, as a consequence of functional and anatomic integrity interruption of BM niches. Given the pivotal role that parathyroid hormone and osteoblasts play in regulating expansion, mobilization and homing of haematopoietic stem/progenitors cells, CKD-MBD could promote CCC formation.

Keywords: atherosclerosis; calcifying circulating cells; chronic kidney disease-mineral and bone disorders; mineral metabolism; vascular calcification.

Fig. 1.

PTH is a pivotal regulator of BM niche and hematopoietic stem cells/circulating precursor cells expansion and mobilization. In the BM, PTH binds to parathyroid hormone 1 receptor (PTH1R) on osteoblasts and drives the expansion of HSPCs. In addition, GCSF inhibits CXCL12 expression, thus promoting HSPC transmigration into the vascular sinuses and so into the bloodstream.

Fig. 2.

The pool of CCCs includes osteoprogenitor (mesenchymal) cells, calcifying EPCs and myeloid calcifying cells. The term CCC identifies several osteogenic cell subsets expressing different yet partly interrelated phenotypes that have a common origin from BM progenitor cells. CCCs are involved in osteogenesis/angiogenesis and in intimal calcification.

Fig. 3.

Putative role of CCCs in intimal, valvular and medial calcification.

Fig. 4.

PTH and CCCs in CKD. The putative link between CKD, CCCs and intimal calcification.