Elucidating Alternative Pathways of Bone Homeostasis

Phillip C. Witcher¹, Lauren E. Deal², Shreya Veera², Alexander G. Robling²

¹Purdue School of Science, Indiana University-Purdue University Indianapolis; ²Department of Anatomy and Cell Biology, Indiana University School of Medicine

Bone health is critical for protecting organs and reinforcing the integrity of the human body. Over 53 million Americans suffer from osteoporosis, a disease characterized by a decrease in bone density. In order to treat such bone disorders, the molecular pathways involved in bone homeostasis may be studied to understand the most effective route for treatment. Previous research has demonstrated a significant link between the WNT pathway and bone remodeling. The canonical WNT pathway, characterized by the binding of a WNT molecule to membrane receptors thereby preventing the degradation of β-catenin, has been extensively studied as a viable pathway for bone remodeling. Besides the canonical pathway, other pathways also participate; PTEN is an intracellular enzyme that inhibits the activity of AKT, an enzyme that has a large impact on the bone forming capacity of osteoblasts. PTEN deletion from osteoblasts results in a high bone mass (HBM) phenotype. Other studies have suggested that PTEN modulates β-catenin activity. However, it is unclear whether the HBM-causing role of PTEN requires intact β-catenin signaling or if PTEN suppression can induce a HBM phenotype independent of β-catenin signaling. In order to test this proposal, four sets of mice were generated with the following genotypes: bone-specific deletion of the PTEN gene, bone-specific deletion of the β-catenin gene, compound bone-specific deletions of PTEN and β-catenin, and wild type controls. The mice were scanned with pQCT and PIXImus machines and injected with four different fluorescent probes at specific intervals to measure the bone growth over sixteen weeks. At the sixteen week time point, the left and right femurs and tibias were removed, along with the 3^rd through 5^th lumbar vertebrae, for additional analysis using pQCT and micro CT scans. This study, still underway, may provide insight into novel pathways involved in bone homeostasis.

Mentor: Alexander G. Robling, Department of Anatomy and Cell Biology, Indiana University School of Medicine

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