Spatial-Temporal Patterns and Inflammatory Factors of Bone Matrix Remodeling

Figure 4

The main regulatory pathways of TGF-β and BMP in bone ECM. TGF-β is produced predominantly by osteoblasts and deposited into the matrix with LAP. Activated TGF-β requires osteoclastic bone resorption by dislodging LAP [67]. Smad2/3 is phosphorylated and connects with Smad4 when TGF-β combines with its receptors. The complex of Smad2/3 with Smad4 could transport into the upstream of Col1α and into other target gene transcription start sites. The complex upregulates gene expressions to promote collagen production [68, 69], and it is inhibited by Smad7. The phosphorylated Smad2/3 could inhibit the expression of Runx2 by combining with HDACs [70]. On the other hand, TGF-β influences Runx2 expression to suppress bone mineralization and osteogenesis by the MAPK pathway, independent of Smad3. The p38 MAPK pathway directly regulates the expression of Runx2. And the MAPK-ERK pathway reduces the expression of Runx2 by upregulating SMAD ubiquitination regulatory factor 1 (SMURF1) [71, 72]. BMP could improve the expression of Runx2 by Smad1/5/8 and Smad4 or the p38 MAPK pathway for regulating skeleton formation [75, 76]. And the process of the combination of Smad4 could suppress the formation of the Smad2/Smad3/Smad4 complex. TGF-β: transforming growth factor β; HDACs: histone deacetylases; ERK1/2: extracellular signal-regulated kinase 1/2; MKK: mitogen-activated protein kinase kinase; TAK1: transforming growth factor-activated kinase 1; SMURF1: SMAD ubiquitination regulatory factor 1; BMP: bone morphogenetic protein; LAP: latency-associated protein; RANKL: receptor activator of nuclear factor kappa B ligand.