Gender difference of CCAAT/enhancer binding protein homologous protein deficiency in susceptibility to osteopenia

Abstract

Expression of CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) is induced during endoplasmic reticulum (ER) stress, which is related to apoptosis in several cell types. CHOP null mice have been exhibited to decrease bone formation. However, a study of transgenic mice overexpressing CHOP in the bone microenvironment showed that CHOP overexpression impairs the osteoblastic function leading to osteopenia. The regulatory role of CHOP in bone formation is controversial and still remains to be clarified. Here, we investigated the alterations in bone microstructure of CHOP knockout (Chop−/−) mice and tested the gender difference of CHOP deficiency in susceptibility to osteopenia. Adult female and male mice (WT) and Chop−/− mice were used. The microcomputed tomography (µCT) analysis in trabecular bone and cortical bone of tibia was determined. Trabecular bone volume fraction (BV/TV), trabecular number, and bone mineral density (BMD) in tibia are markedly decreased in both male and female Chop−/− mice compared to the control WT mice. Unexpectedly, the BMD and BV/TV in trabecular bone of tibia in female Chop−/− mice were significantly lower than in male Chop−/− mice. The similar results could also be observed in the cortical bone of tibia in Chop−/− mice. This gender difference was also observed in the decreased capacity of osteoblast differentiation of bone marrow cells isolated from Chop−/− mice. These results indicated that ER stress‐related CHOP signaling might play an important role in the bone formation in a mouse model, especially in females. There is the gender difference of CHOP deficiency in susceptibility to osteopenia. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

The Role of Sex Differences in Bone Health and Healing

“…CHOP deficiency alters BMD, bone microstructure and osteoblastogenesis, indicating that ER stress-related CHOP signaling suppresses cell cycle progression and may play an important role in bone formation in mice, especially in female mice. Further studies are needed to clarify whether the estrogenic signaling pathway could be involved in the observed sex differences in CHOP-mediated susceptibility to osteopenia [74].…”

Endoplasmic reticulum stress: a novel targeted approach to repair bone defects by regulating osteogenesis and angiogenesis

“…Excessive ER stress inhibits osteogenic differentiation and induces their apoptosis [ 91 , 95 , 96 ], which is an important mechanism of osteoporosis [ 97 ]. The effect may be related to the overexpression of CHOP caused by excessive ER stress [ 98 ], and there are sex differences in sensitivity to CHOP [ 99 ]. Overexpression of CHOP reduces alkaline phosphatase activity and calcified bone nodule formation [ 100 ], and initiates osteoblast apoptosis, inhibits bone formation, and induces osteopenia [ 98 , 100 ].…”