Apoptosis in the Extraosseous Calcification Process

Abstract

Extraosseous calcification is a pathologic mineralization process occurring in soft connective tissues (e.g., skin, vessels, tendons, and cartilage). It can take place on a genetic basis or as a consequence of acquired chronic diseases. In this last case, the etiology is multifactorial, including both extra- and intracellular mechanisms, such as the formation of membrane vesicles (e.g., matrix vesicles and apoptotic bodies), mitochondrial alterations, and oxidative stress. This review is an overview of extraosseous calcification mechanisms focusing on the relationships between apoptosis and mineralization in cartilage and vascular tissues, as these are the two tissues mostly affected by a number of age-related diseases having a progressively increased impact in Western Countries.

Keywords: apoptosis; cartilage; cell death; ectopic mineralization; extracellular matrix; vascular tissue.

Figure 1

MVs. Mineral deposition is initiated by accumulation of calcium (Ca²⁺) and inorganic phosphate (PO₄³⁻) into matrix vesicles (MVs) (for more details see the text) Abbreviations: ANKH = progressive ankylosis protein homolog, ANX = annexin; ENPP1 = nucleotide pyrophosphatase phosphodiesterase; OPN = osteopontin; PC = phosphocholine; PiT = phosphate transporter; P₂O₇⁴⁻ = pyrophosphate; PS = phosphatidylserine; TNAP = tissue non-specific alkaline phosphatase; SM = sphingomyelin.

Figure 2

(A) Generation of ROS and RNS. When ROS and RNS production exceeds the capacity of antioxidant systems, an oxidative stress condition is created, which causes damage to the macromolecules (i.e., nucleic acids, proteins, carbohydrates, and lipids). (B) Signal transduction pathways regulated by ROS and RNS. The activation of these pathways induces nuclear translocation of transcription factors, which lead to the activation of osteogenic genes. Abbreviations: ROS = reactive oxygen species; RNS = reactive nitrogen species; BMP-2/4 = bone morphogenetic protein-2 and -4, CAT = catalase, GPX = glutathione peroxidase, GSH = reduced glutathione, GSR = glutathione disulfide reductase, GSSG = glutathione disulfide, H₂O₂ = hydrogen peroxide, O₂^●− = superoxide anion, ^●OH = hydroxyl radical, ONOO⁻ = radical peroxynitrite, Msx2 = muscle segment homeobox 2, ^●NO = nitric oxide, ^●NO₂ = nitrogen dioxide radical; NO₃⁻ = nitrate; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells, PI3K/Akt = phosphatidylinositol 3-kinase/protein kinase-B, PRDX = peroxiredoxin, Runx2 = runt-related transcription factor 2, SOD = superoxide dismutase, Trx_red = reduced thioredoxin, Trx_ox = oxidized thioredoxin, TrxR = thioredoxin reductase.

Figure 3

Schematic representation of extrinsic and intrinsic factors involved in chondrocyte apoptosis. Abbreviations: ADAMTS = disintegrin and metalloproteinase with thrombospondin motifs; AGE = advanced glycation end products; Bax = Bcl-2-associated X; Bcl-2 = B-cell lymphoma protein 2; Cyt c = cytochrome c; ΔΨ = mitochondrial membrane potential, ECM = extracellular matrix; ERK = extracellular-signal-regulated kinase; FasL = Fas ligand; HNE = 4-hydroxynonenal; IL-1β = interleukin 1 beta; iNOS = inducible nitric oxide synthases; JNK = c-Jun N-terminal kinases; LncRNAs = long non-coding RNA; MAPK = mitogen-activated protein kinase; miRNAs = microribonucleic acids; MMP = matrix metalloproteinases; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells; NO = nitric oxide; ONOO⁻ = radical peroxynitrite, OX = oxidative stress; PI3K/Akt = phosphatidylinositol 3-kinase/protein kinase-B; RAGE = receptor for advanced glycation end products, ROS = reactive oxygen species; SOD = superoxide dismutase; TNF-α = tumor necrosis factor alpha.