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Figure 1 | Orphanet Journal of Rare Diseases

Figure 1

From: Perturbation of specific pro-mineralizing signalling pathways in human and murine pseudoxanthoma elasticum

Figure 1

Schematic representation of the pathways (1–10) involved in vascular soft tissue mineralization. Vascular calcification is the result of a transdifferentiation process of vascular smooth muscle cells (VSMCs) to chondrocyte-like or osteoblast-like cells [18]. (1) BMP2 and BMP4 induce osteogenic differentiation through SMAD dependent signal transduction. BMP2/4 ligands bind with BMP receptors BMPR-I and BMPR-II; BMPR-II then phosphorylates and activates BMPR-I. Phosphorylated BMPR-I subsequently phosphorylates SMAD1, SMAD5 and SMAD8 (SMAD1, 5, 8) which associate with SMAD4 to form the heteromeric pSMAD1,4,5,8. This facilitates nucleation, where they regulate the pro-osteogenic runt-related transcription factor RUNX2 [19]. Downstream targets of RUNX2 include osterix (OSX), alkaline phosphatase (ALPL or TNAP), osteopontin (OPN), osteocalcin (OC) and collagen type-1 (Col-1) [20]. (2) TGF-βs (1-2-3) bind to TGF-β receptor type I or II, resulting in phosphorylation of SMAD2/3, coupling with SMAD4 and translocation into the nucleus [21–23], where they trigger targeted gene expression of connective tissue growth factor (CTGF) [24–26]. (3) BMP7 activates endogenous SMAD1,5,8 and forms a SMAD1,4,5,8 complex, facilitating nucleation and stimulation of VSMC specific genes (SM-MHC, SM actin, MGP, Id-2). Through SMAD6 and SMAD7, BMP7 also inhibits BMP2 and TGF-β signalling [27]. (4) Elevated inorganic phosphate (Pi) enters the cell via sodium-dependent phosphate co-transporters PiT-1 and 2, resulting in downregulation of mineralization inhibitors, apoptosis (through downregulation of GAS6 and BCL-2, thus activating caspases), and upregulation of RUNX2 through ERK1/2 activation [28–30]. (5) MSX2 upregulates different Wnt receptors, causing stabilization of β-catenin, which after nucleation increases TCF-1/LEF-1 dependent gene expression. This in turn can upregulate MSX2 expression [31]. (6) DLX5 drives RUNX2 expression and osteogenic differentiation, and can abrogate osterix induction by BMP2. DLX5 also negatively regulates the activity of MSX2 [32]. (7) ER stress initiates a cascade of chaperone proteins leading to activation of caspases such as Caspase 12 and apoptosis (so-called unfolded protein response) [33]. (8) BMP2 can directly increase expression of ERK1/2, thus increasing RUNX2 expression and SMC phenotypic transition toward osteochondro-progenitors [34]. (9) Oxidative stress and inflammatory mediators respond with higher BMP2/4 secretion in VSMCs calcification process [35, 36]. (10) Tissue nonspecific alkaline phosphatase (TNAP or ALPL) has a major role both as a PPiase and as an ATPase/ADPase and thus participates in the calcification process by restricting the concentration of extracellular PPi, a calcification inhibitor. Nucleotide pyrophosphatase phosphodiesterase 1 (NPP1) works as a backup for PPiase and ATPase, especially in the absence of [27].

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