ADAM17 Controls Endochondral Ossification by Regulating Terminal Differentiation of Chondrocytes
Year: 2013
Type: article
Abstract: Endochondral ossification is a highly regulated process that relies on properly orchestrated cell-cell interactions in the developing growth plate. This study is focused on understanding the role of a crucial regulator of cell-cell interactions, the membrane-anchored metalloproteinase ADAM17, in endochondral ossification. ADAM17 releases growth factors, cytokines, and other membrane proteins from cells and is essential for epidermal growth factor receptor (EGFR) signaling and for processing tumor necrosis factor alpha. Here, we report that 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 produces 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 transforming growth factor α (TGFα), suggesting that ADAM17 regulates terminal differentiation of chondrocytes during endochondral ossification by activating the TGFα/EGFR signaling axis.
Source: Molecular and Cellular Biology
DOI: 10.1128/mcb.00291-13
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Institutes of Health, National Institute on Aging, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1188549032, G1714883407, Mechanisms of Pbx-directed Genetic & Transcriptional Control of Limb Development, Pancreatic Tumor Progression in the Absence of ADAM-mediated alpha-secretase Acti, ESE 1 a novel transcriptional regulator of cartilage remodeling, Defining Common Molecular Parameters For Onset and Progression of Osteoarthritis, Musculoskeletal Training Program, EXTRAMURAL RESEARCH FACILITIES CONSTRUCTION, ADAM17 in pancreatic cancer and pancreatitis, iRhoms 1 and 2: Key regulators of ADAM17-dependent EGFR signaling, Musculoskeletal Repair and Regeneration
OpenAlex ID: W2159555403