Epidermal growth factor receptor regulates osteoclast differentiation and survival through cross‐talking with RANK signaling

Abstract

The epidermal growth factor receptor (EGFR) functions in various cellular physiological processes such as proliferation, differentiation, and motility. Although recent studies have reported that EGFR signaling is involved in osteoclast recruitment and formation, the molecular mechanism of EGFR signaling for the regulation of osteoclastogenesis remains unclear. We investigated the role of the EGFR in osteoclast differentiation and survival and show that the expression of the EGFR was highly up-regulated by receptor activator of nuclear factor-kappaB ligand (RANKL) during osteoclast differentiation. EGFR-specific tyrosine kinase inhibitors and EGFR knockdown blocked RANKL-dependent osteoclast formation, suggesting that EGFR signaling plays an important role in osteoclastogenesis. EGFR inhibition impaired the RANKL-mediated activation of osteoclastogenic signaling pathways, including c-Jun N-terminal kinase (JNK), NF-kappaB, and Akt/protein kinase B (PKB). In addition, EGFR inhibition in differentiated osteoclasts caused apoptosis through caspase activation. Inhibition of the phosphoinositide-3 kinase (PI3K)-Akt/PKB pathway and subsequent activation of BAD and caspases-9 and -3 may be responsible for the EGFR inhibition-induced apoptosis. The EGFR physically associated with receptor activator of nuclear factor-kappaB (RANK) and Grb2-associated binder 2 (Gab2). Moreover, RANKL transactivated EGFR. These data indicate that EGFR regulates RANKL-activated signaling pathways by cross-talking with RANK, suggesting that the EGFR may play a crucial role as a RANK downstream signal and/or a novel type of RANK co-receptor in osteoclast differentiation and survival.

Enhanced osteoinductivity of recombinant human bone morphogenetic protein-2 in combination with epidermal growth factor in a rabbit tibial defect model

“…These results are consistent with previous reports showing that EGFR signaling regulates osteoclast formation and play roles in osteoclast differentiation and survival by cross-talking with RANK signaling pathways (Wang et al, 2004;Yi et al, 2008). However, excessive osteoclastogenesis can disrupt bone formation and trabeculation remodeling, which are processes requiring properly controlled osteoblast differentiation and osteoclastogenesis.…”

Accelerated and increased joint damage in young mice with global inactivation of mitogen-inducible gene 6 after ligament and meniscus injury

“…EGFR signaling is important for osteoclastogenesis; therefore, tartrate-resistant acid phosphatase (TRAP) staining was performed with a kit obtained from Sigma-Aldrich (St Louis, MO, USA) according to manufacturer’s instructions to detect osteoclasts [36]. A terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling (TUNEL) assay was performed according to the manufacturer’s instructions to assess cellular apoptosis (Promega, Madison, WI, USA).…”

Ligand-Dependent Activation of EGFR in Follicular Dendritic Cells Sarcoma is Sustained by Local Production of Cognate Ligands

“…In the hematopoietic system EGFR is functional only on subsets of monocyte-derived cells, namely osteoblasts and osteoclasts (9). In contrast, all the remaining lineages are independent from this receptor for their biological activities.…”