Rationale for the role of osteoclast‐like cells in arterial calcification

Abstract

Atherosclerotic arteries frequently become calcified, and these calcium deposits are associated with a high risk of adverse clinical events. Descriptive studies suggest calcification is an organized and regulated process with many similarities to osteogenesis, yet the mechanism and its relationship to atherosclerosis remain largely unknown. In bone development and homeostasis, mineral deposition by osteoblasts and mineral resorption by osteoclasts are delicately balanced such that there is no overall gain or loss in bone mass. We hypothesize that there exists in arteries a mechanism that similarly balances mineral deposition with resorption. We propose that the cellular mediators of arterial mineral resorption are osteoclast-like cells (OLCs) derived from hematopoietic precursors of the mononuclear phagocytic lineage. In arterial microenvironments, mononuclear precursors are induced to differentiate toward OLCs by macrophage-colony stimulating factor and receptor activator of NF-kappaB ligand, both of which are necessary and sufficient for osteoclastogenesis and mineral resorption in bone. OLCs may participate in normal mineral homeostasis within the arterial wall or, alternatively, may be recruited to specific sites within developing plaque. Net calcium deposition occurs as a result of focal perturbation of the balance between the activity of osteoblast-like cells and OLCs. Our proposed mechanism thus views arterial mineral deposition not so much as an active pathological process, but as a localized failure of protective mechanisms that actively oppose mineral deposition within the disordered metabolic milieu of developing atherosclerotic plaque.

Calcification in atherosclerosis: Bone biology and chronic inflammation at the arterial crossroads

“…We have proposed that calcium deposition might be importantly determined by the activity of osteoclast-like cells (OLCs), arterial cells with the capacity to inhibit calcium deposition and͞or resorb mineral (ref. 36 and Fig. 3).…”

“…Deletion of the gene encoding RANKL or RANK results in nearly a complete lack of functional osteoclasts, and RANKL and CSF-1 signaling are necessary and sufficient for osteoclast survival and function. Several lines of evidence support a role for CSF-1 and RANKL signaling in the development of arterial OLCs from plaque mononuclear phagocytes (36). RANKL and its receptors are expressed in a number of vascular tissues, including arteries, and their expression patterns are altered as plaque forms and mineral deposits appear.…”

Shift of Macrophage Phenotype Due to Cartilage Oligomeric Matrix Protein Deficiency Drives Atherosclerotic Calcification

“…Previously, osteoclast-like cells, differentiated from hematopoietic precursors of the mononuclear phagocyte lineage, have been proposed to be able to remove artery wall mineral deposits for cell-based therapy because osteoclasts reduced the mineral content of calcified elastin in vitro 35 and because osteoclast-like cells in calcified atherosclerotic lesions from humans and mice are decreased after atherosclerotic calcification. 36 However, with the recognition of the osteoprotegerin/receptor activator of nuclear factor-κB triad/receptor activator of nuclear factor-κB ligand triad in calcification of the atheromatous plaques, contradictory results were reported. Knockout of osteoprotegerin, the inhibitor of receptor activator of nuclear factor-κB ligand-dependent osteoclast formation, leads to reduced lesion calcification.…”

The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD

“…Resorption of existing deposits at a rate greater than formation (adding to or creating new deposits) is the most reasonable explanation of our results. Because tartrate resistant acid phosphatase (TRAP)-positive multinucleated osteoclast-like cells have been demonstrated in the neointima, 14,45,46 we interpreted the decrease in the vascular mineralization in CaCO 3 -and BMP-7-treated animals to be compatible with decreased formation of vascular mineral deposits and continued resorption.…”