Abstract
ABSTRACTHB‐EGF, a member of the EGF superfamily, plays important roles in development and tissue regeneration. However, its functions in skeletal stem cells and skeleton development and growth remain poorly understood. Here, we used the Cre/LoxP system to ablate or express HB‐EGF in Dermo1+ mesenchymal stromal cells and their progenies, including chondrocytes and osteoblast lineage cells, and bone marrow stromal cells (BMSCs). Dermo1‐Cre; HB‐EGFf/f mice only showed a modest increase in bone mass, whereas Dermo1‐HB‐EGF mice developed progressive chondrodysplasia, chondroma, osteoarthritis‐like joint defects, and loss of bone mass and density, which were alleviated by treatment with EGFR inhibitor AG1478. The cartilage defects were recapitulated in chondrocyte‐specific HB‐EGF overexpression (Col2‐HB‐EGF) mice with a lesser severity. Dermo1‐HB‐EGF mice showed an increase in proliferation but defects in differentiation of chondrocytes and osteoblasts. HB‐EGF promoted BMSC proliferation via the Akt1 and Erk pathways but inhibited BMSC differentiation via restraining Smad1/5/8 activation. However, Dermo1‐HB‐EGF mice showed normal osteoclastogenesis and bone resorption. These results reveal an important function of autocrine or paracrine HB‐EGF in mesenchymal stromal cell proliferation and differentiation and suggest that EGF signaling needs to be tightly controlled to maintain bone and articular cartilage integrity. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
Highlights
Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF superfamily that includes EGF, TGFa, and amphiregulin, with HB-EGF having high affinity for heparin
Knockout of EGFR results in delayed formation of the secondary ossification center and recruitment of osteoblasts and osteoclasts, leading to osteoporosis.[21] osteoblastspecific EGFR knockout mice (Col1-Cre; EGFRf/f) showed no skeletal phenotypes, overexpression of a dominant negative EGFR mutant in osteoblasts led to a decrease in the number of osteoblasts and an increase in the number of osteoclasts, resulting in osteoporosis.[22]. In addition, overexpression of the dominant negative EGFR in Col2þ chondrocytes leads to defects in chondrocyte proliferation and survival and development of osteoarthritis, and EGFR signaling has been proposed as a target to prevent osteoarthritis development.[23,24,25] These results suggest that EGFR signaling plays an anabolic role in skeletal development through promoting proliferation of osteoblasts and chondrocytes
Western blot results showed that the HB-EGF levels went down when bone marrow stromal cells (BMSCs) differentiated into osteoblasts in vitro, which was monitored with ALP staining (Fig. 1A, B and Supplemental Fig. S1A)
Summary
Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF superfamily that includes EGF, TGFa, and amphiregulin, with HB-EGF having high affinity for heparin. HBEGF is cloned from monocytes and macrophages and is synthesized as a membrane-anchored glycoprotein.[1] Ectodomain shedding by proteases generates the soluble form of HBEGF, which can function in autocrine and paracrine fashions.[2,3] The membrane-bound HB-EGF can function in juxtacrine signaling Both soluble and membrane-bound HB-EGF participates in normal physiological processes.[4,5] HB-EGF binds to EGF receptor (EGFR, ErbB1) and ErbB4, leading to activation of Akt, Erk, and other pathways to promote cell proliferation, survival, and migration.[6,7] Interestingly, membrane-bound HB-EGF serves as a receptor for diphtheria toxin (DTR).(8). The roles of HB-EGF signaling in development of the skeleton and the etiology of related diseases remain unclear and need further investigation
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