Glucocorticoid induced bone disorders in children: Research progress in treatment mechanisms

Abstract

Long-term or supra-physiological dose of glucocorticoid (GC) application in clinic can lead to impaired bone growth and osteoporosis. The side effects of GC on the skeletal system are particularly serious in growing children, potentially causing growth retardation or even osteoporotic fractures. Children's bone growth is dependent on endochondral ossification of growth plate chondrocytes, and excessive GC can hinder the development of growth plate and longitudinal bone growth. Despite the availability of drugs for treating osteoporosis, they have failed to effectively prevent or treat longitudinal bone growth and development disorders caused by GCs. As of now, there is no specific drug to mitigate these severe side effects. Traditional Chinese Medicine shows potential as an alternative to the current treatments by eliminating the side effects of GC. In summary, this article comprehensively reviews the research frontiers concerning growth and development disorders resulting from supra-physiological levels of GC and discusses the future research and treatment directions for optimizing steroid therapy. This article may also provide theoretical and experimental insight into the research and development of novel drugs to prevent GC-related side effects.

Keywords: bone growth suppression; chondrocyte 3; glucocorticoid (GC); growth hormone; growth plate.

Figure 1

Effects of glucocorticoid (GC) on endocrine hormones and cytokines. (1) GC decreases growth hormone (GH) and insulin growth factor-1 (IGF-1) levels which in turn inhibits the chondrocyte proliferation. (2) GC affects thyroid hormone secretion and further inhibits the chondrocyte hypertrophy. (3) GC decreases Indian hedgehog factor (IHH) secretion and then inhibits chondrocyte proliferation and increases chondrocyte apoptosis. (4) GC constrains C-type natriuretic peptide (CNP) production, which controlling the entry of calcium ion into chondrocytes to stimulate growth. (5) GC causes hypocalcemia through upregulation of fibroblast growth factor 23 (FGF23) expression in bone and plasma, which in turn inhibits chondrocyte proliferation. (6) GC inhibits estrogen (E2) secretion, causing decreased osteoclast activity and increased osteoblast apoptosis.

Figure 2

Overview of glucocorticoid-induced chondrocyte apoptosis and matrix synthesis reduction. (1) Glucocorticoid (GC) induces direct binding of glucocorticoid receptor (GR) to the uridine diphosphate glucose dehydrogenase (UGDH) promoter in chondrocytes and suppresses UGDH gene expression, a change that further resulted in a reduced synthesis of proteoglycans (PGs) in developing chondrocytes. (2) GC causes cell cycle inhibition by suppressing the promyelocytic leukemia zinc finger (PLZF) gene. (3) Glucocorticoid-induced activation of Bax and its translocation to the mitochondrial membrane leads to subsequent induction of apoptosis. (4) GC causes a decrease in the anti-apoptotic proteins Bcl-2 and Bcl-x in growth plate chondrocytes. (5) GC inhibits KLF2 expression which regulating the Runx2-mediated PI3K/AKT and Erk signaling pathways responsible for the chondrocyte apoptosis.