Loss of transcription factor early growth response gene 1 results in impaired endochondral bone repair

Abstract

Transcription factors that play a role in ossification during development are expected to participate in postnatal fracture repair since the endochondral bone formation that occurs in embryos is recapitulated during fracture repair. However, inherent differences exist between bone development and fracture repair, including a sudden disruption of tissue integrity followed by an inflammatory response. This raises the possibility that repair-specific transcription factors participate in bone healing. Here, we assessed the consequence of loss of early growth response gene 1 (EGR-1) on endochondral bone healing because this transcription factor has been shown to modulate repair in vascularized tissues. Model fractures were created in ribs of wild type (wt) and EGR-1−/− mice. Differences in tissue morphology and composition between these two animal groups were followed over 28 post fracture days (PFDs). In wt mice, bone healing occurred in healing phases characteristic of endochondral bone repair. A similar healing sequence was observed in EGR-1−/− mice but was impaired by alterations. A persistent accumulation of fibrin between the disconnected bones was observed on PFD7 and remained pronounced in the callus on PFD14. Additionally, the PFD14 callus was abnormally enlarged and showed increased deposition of mineralized tissue. Cartilage ossification in the callus was associated with hyper-vascularity and -proliferation. Moreover, cell deposits located in proximity to the callus within skeletal muscle were detected on PFD14. Despite these impairments, repair in EGR-1−/− callus advanced on PFD28, suggesting EGR-1 is not essential for healing. Together, this study provides genetic evidence that EGR-1 is a pleiotropic regulator of endochondral fracture repair.

The Immediate Early Gene Product EGR1 and Polycomb Group Proteins Interact in Epigenetic Programming during Chondrogenesis

“…Published work on a conventional molecular genetic gene knock-out model for mouse Egr1 ( NgfiA, Krox24, Zif268 ) revealed no abnormalities in chondrogenic capacity [24]. A similar discrepancy between in vivo and in vitro findings was reported for EGR1s' role in retinal mircogliosis [57].…”

“…In addition, PRC control inflammatory responses [56] providing an additional potential function link between these cellular functions. Thus, although EGR1 has been implicated in several clinical aspects of cartilage physiology, its direct contribution to chondrogenesis was not known [17], [24], [54].…”

“…The gene products of Early Growth Response ( EGR ) gene family, EGR1 (KROX24/NGFI-A/TIS8/zif268), EGR2 (KROX20, CMT4E), EGR3 and EGR4 (NGFI-C) have been implicated in several neuro-muscular and musculo-skeletal processes [19]–[23]. Molecular genetic mouse models support a potential pleiotropic regulatory function for EGR1 in endochondral ossification, based on abnormal fracture callus formation and mineralization [24], [25], but fail to pinpoint a role for EGR1 in chondrogenesis, most likely due to redundant action of EGR family proteins. Although these observations support a potential role for EGR1 in cartilage physiology, a role for EGR1 in chondrogenesis remained to be elucidated.…”

Molecular changes in peripheral blood involving osteoarthritic joint remodelling

“…EGR1 is a transcription factor for growth and differentiation and serves as a regulator in several biological processes . EGR1 is involved in responding to mechanical stress in bone cells and wound‐healing processes such as the healing of vessels, cartilages and bones . It can be detected in the callus in multiple tissues, such as lung injuries, endothelial wounds, vascularised tissue and bone fractures .…”

Tendons and Ligaments: Connecting Developmental Biology to Musculoskeletal Disease Pathogenesis

“…Mechanical force and misexpression of Scx synergistically promoted the differentiation of human MSCs to tenocytes . Egr1/2 was also increased after short treadmill exercise in rats, and the forced expression of Egr1 rescued tendon gene downregulation during tendon healing under conditions of a reduced mechanical load …”