Unmet NeedChildhood and adolescence are critical periods for bone growth and mineral accrual. Bone mass and strength in this period are influenced by genetic/epigenetic factors, activity, nutrition, and hormones. For children with genetic skeletal disorders or chronic disease, bone growth and mineral accrual are often compromised, leading to osteoporosis and large number bone fractures. Osteoporosis during childhood development is divided into primary and secondary causes, with osteogenesis imperfecta representing primary osteoporosis. Secondary pediatric osteoporosis caused by underlying diseases and/or their treatment fall into two broad categories: 1) glucocorticoid-induced disease and 2) weight-bearing or mobility disorders.
Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis. Long-term treatment with glucocorticoids has been widely used in the management of chronic inflammatory childhood illnesses. Despite improved outcomes and survival rates, there can be substantial adverse effects on general bone health and growth. Epidemiological studies revealed that children and young adults with long-term exposure to glucocorticoid therapy are subject to a ~34% prevalence for vertebral fractures. To date, no treatment modality exists that can protect healthy bone growth and mineral accrual during childhood glucocorticoid treatment.
Technology OverviewJohns Hopkins researchers identified and characterized a selective H3K27 demethylase inhibitor for the therapeutic treatment of pediatric and juvenile osteoporosis induced by glucocorticoid therapy. Using mouse models, the investigators discovered that the normal programmed senescence of bone mesenchymal stem/progenitor cells is under the epigenetic control of the histone methyltransferase enhancer, Ezh2, and its methylation of histone H3, H3K27.
The researchers found that the deletion of the
Ezh2 methyltransferase gene induced premature cellular senescence during early puberty, which led to osteogenesis and late bone loss. Similarly in normal mice during early puberty, treatment with glucocorticoids induced early cellular senescence in the long bone. The inventors describe a treatment method that uses the H3K27-specific demethylase inhibitor, GSK-J4, which elevates H3K27 methylation and subsequently blocks the early onset of cellular senescence and rescues the bone-loss phenotype induced by glucocorticoid treatment.
Stage of DevelopmentIn vivo data is available.
PublicationsLi C, et al. Nature Communications 8: 1312, 2017
