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Review
. 2022 Jan 7;118(1):84-96.
doi: 10.1093/cvr/cvaa299.

TNAP as a therapeutic target for cardiovascular calcification: a discussion of its pleiotropic functions in the body

Claudia Goettsch  1 , Agnieszka Strzelecka-Kiliszek  2 , Laurence Bessueille  3 , Thibaut Quillard  4 , Laura Mechtouff  5   6 , Slawomir Pikula  2 , Emmanuelle Canet-Soulas  7 , Jose Luis Millan  8 , Caroline Fonta  9 , David Magne  3
Affiliations
Review

TNAP as a therapeutic target for cardiovascular calcification: a discussion of its pleiotropic functions in the body

Claudia Goettsch et al. Cardiovasc Res. .

Erratum in

Abstract

Cardiovascular calcification (CVC) is associated with increased morbidity and mortality. It develops in several diseases and locations, such as in the tunica intima in atherosclerosis plaques, in the tunica media in type 2 diabetes and chronic kidney disease, and in aortic valves. In spite of the wide occurrence of CVC and its detrimental effects on cardiovascular diseases (CVD), no treatment is yet available. Most of CVC involve mechanisms similar to those occurring during endochondral and/or intramembranous ossification. Logically, since tissue-nonspecific alkaline phosphatase (TNAP) is the key-enzyme responsible for skeletal/dental mineralization, it is a promising target to limit CVC. Tools have recently been developed to inhibit its activity and preclinical studies conducted in animal models of vascular calcification already provided promising results. Nevertheless, as its name indicates, TNAP is ubiquitous and recent data indicate that it dephosphorylates different substrates in vivo to participate in other important physiological functions besides mineralization. For instance, TNAP is involved in the metabolism of pyridoxal phosphate and the production of neurotransmitters. TNAP has also been described as an anti-inflammatory enzyme able to dephosphorylate adenosine nucleotides and lipopolysaccharide. A better understanding of the full spectrum of TNAP's functions is needed to better characterize the effects of TNAP inhibition in diseases associated with CVC. In this review, after a brief description of the different types of CVC, we describe the newly uncovered additional functions of TNAP and discuss the expected consequences of its systemic inhibition in vivo.

Keywords: Inflammation; Cardiovascular calcification; Inhibition; Therapeutic target; Tissue non-specific alkaline phosphatase.

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Figures

None
Graphical abstract
Figure 1
Figure 1
Structural features of TNAP. AMP, adenosine monophosphate; ATP, adenosine triphosphate; GPI, glycosyl phosphatidyl inositol; LPS, lipopolysaccharide; OPN, osteopontin; PPi, inorganic pyrophosphate; PLP, pyridoxal phosphate; TNAP, tissue-nonspecific alkaline phosphatase. Modified from Ref.
Figure 2
Figure 2
TNAP’s involvement in PPi dephosphorylation leading to the mineralization of collagen-rich tissues (A) and in AMP dephosphorylation leading to resolution of inflammation (B). Ado, adenosine; AMP, adenosine monophosphate; ANKH, progressive ankylosis protein homolog; ATP, adenosine triphosphate; ENPP1, ectonucleotidase pyrophosphatase phosphodiesterase 1; Pi, inorganic phosphate; PPi, inorganic pyrophosphate; TNAP, tissue-nonspecific alkaline phosphatase; VSMC, vascular smooth muscle cell.
Figure 3
Figure 3
TNAP activity detected by histochemistry in E15 mouse embryo (bar 500 µm). Taken with permission from Ref.
See this image and copyright information in PMC

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