Treatment of Osteoporosis in Murine Rett Syndrome Models

Principal Investigator: Jay Shapiro

Sponsored by the International Rett Syndrome Foundation.

At the Kennedy Krieger Institute, approximately 50 percent of young children and adults with Rett syndrome (RTT) have osteoporosis; 11 percent of these patients have suffered fractures. RTT is associated with mutations involving MECP2 and FOXG1 genes. The effect of these mutations on bone cell function has not been defined. Histological studies in murine models of RTT and bone biopsies from a small series of RTT patients suggest that MECP2 mutations impair osteoblastic bone formation. Bisphosphonates, which inhibit osteoclastic bone resorption, are used to treat osteoporotic disorders in children and adults. A treatment for decreased bone mass in RTT patients has not been studied. It is not clear whether teriparatide, which increases osteoblastic bone formation, or zoledronic acid, which limits osteoclast activity, would be more effective in improving bone mass and protecting against fractures in patients with RTT. Our preliminary studies in the Adrian Bird RTT mouse model indicate heterozygous (HET) and hemizygous (MECP2-null) mice have reduced trabecular bone volume compared to the wild type (WT). Our in vitro data shows increased cell proliferation in cultured osteoblasts in HET and MECP2-null mice; WT osteoblast cells express MeCP2 protein but not those from MECP2-null mice.

The goal of this study is to evaluate the efficacy of two drugs that target bones in the Adrian Bird RTT model, to better define treatment options for children and adults with RTT. We propose to administer parenteral teriparatide and zoledronic acid for four weeks starting at four weeks of age in MECP2-null mice and for six weeks beginning at eight weeks in HET mice, to:

  1. Study the effects on bone mass and bone histomorphology
  2. Determine the in vitro effects of these agents on osteoblast growth rates, type I collagen and alkaline phosphatase production
  3. Study the in vitro effects of drug treatment on MECP2 and FOXG1 and related gene expression in murine osteoblast cells using CHIP-microarray methodology

Non-treated control groups (WT, HET, and MECP2-null mice) are included. Treatments will be considered efficacious if they increase bone cell function and bone mass in these models. We cannot predict which agent will prove more effective in increasing bone mass or in decreasing fracture rate.