ADAM17

ADAM17 controls endochondral ossification by regulating terminal differentiation of chondrocytes.

"mice lacking ADAM17 in chondrocytes (A17ΔCh) have a significantly expanded zone of hypertrophic chondrocytes in the growth plate and retarded growth of long bones. This abnormality is caused by an accumulation of the most terminally differentiated type of chondrocytes that produce a calcified matrix. Inactivation of ADAM17 in osteoclasts or endothelial cells does not affect the zone of hypertrophic chondrocytes, suggesting that the main role of ADAM17 in the growth plate is in chondrocytes. This notion is further supported by in vitro experiments showing enhanced hypertrophic differentiation of primary chondrocytes lacking Adam17. The enlarged zone of hypertrophic chondrocytes in A17ΔCh mice resembles that described in mice with mutant EGFR signaling or lack of its ligand TGFα, suggesting that ADAM17 regulates terminal differentiation of chondrocytes during endochondral ossification by activating the TGFα/EGFR signaling axis."

"Mice carrying the human EGFR, instead of the mouse receptor, have an enlarged zone of hypertrophic cells, presumably because the human EGFR is only weakly expressed, thereby generating a partial loss-of-function mutation"

"treatment of one-month-old rats with the EGFR inhibitor, gefitinib{more on EGFR and gefitinb}, results in a profound expansion of the growth plate, caused by an increased size of the hypertrophic zone. This treatment reduces the MMP9, MMP13, and MMP14 levels at the chondro-osseus junction (COJ) and causes a defect in osteoclast migration to the COJ, presumably due to altered levels of RANKL and OPG released by hypertrophic chondrocytes"

"[ADAM17 is] the principal sheddase for five EGFR-ligands: heparin binding-epidermal growth factor (HB-EGF), transforming growth factor α (TGFα), amphiregulin, epiregulin and epigen"  Sheddases release soluble ectodomains from the cell surface.

"The related ADAM10 is required for shedding of the remaining two ligands: betacellulin and EGF"

"Tgfα-/- mice display a [growth plate] phenotype remarkably similar to that of EGFR inhibitor-treated rats"

"When we measured the length of bones at different stages of development, we found that the long bones of A17ΔCh mice were significantly shorter than those of control mice starting at P14 and P21. The femora and tibiae of A17ΔCh adults (20-week old) were 5% shorter than those of littermate controls"