The role of plastin-3 in skeletal remodeling

• Applicants: Professor Dr. Michael Amling; Professor Thorsten Schinke, Ph.D.
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 385501541

The skeleton is a highly complex tissue being constantly remodeled in a process mediated by the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. A relative increase of bone resorption is the cause of osteoporosis, one of the most prevalent disorders in the aged population. We have previously identified two individuals with early-onset osteoporosis (EOOP) carrying mutations of the PLS3 gene, thereby confirming previous studies describing hemizygous inactivating PLS3 mutations as a cause of X-linked osteoporosis and heterozygous PLS3 mutations in women with EOOP. How Pls3 is involved in skeletal remodeling is still unknown, yet it has been suggested that the protein might be required for morphological changes associated with osteoblast to osteocyte transition. Whether this is truly the primary function of Pls-3 in skeletal remodeling however remains to be determined, and the same applies for potential effects of Pls3 inactivation on other cell types. This paucity of knowledge is likely explained by the lack of studies describing the generation and phenotyping of Pls3-deficient mice. To analyze the impact of Pls3 inactivation on bone mass at a cellular and molecular level we took advantage of a commercially available Pls3-deficient mouse model from EUCOMM. Until now we have analyzed the first set of 6 weeks and 12 weeks old Pls3-/0 males and their corresponding Pls3+/0 littermates by µCT scanning of the femora. Here we could clearly demonstrate that Pls3-deficiency affects bone mass, primarily in the cortical compartment, thereby providing the basis for several additional experiments. More specifically, we will compare the phenotype of Pls3-/0 males and Pls3+/- females towards wildtype littermates at various ages using static, cellular and dynamic histomorphometry, paired with gene expression studies and serum analysis for bone remodeling biomarkers. We will also analyze the impact of Pls3 inactivation on the osteocyte network, and we will study the behavior of Pls3-deficient bone cells (osteoblasts and osteoclasts) ex vivo. Finally, we will utilize this mouse model in order to optimize the treatment for individuals with X-linked osteoporosis due to PLS3 mutation. Since we have previously used most of these methods for other projects, we expect to obtain significant insights into the role of role of plastin-3 in skeletal remodeling within the next 36 months.

• DFG Programme: Research Grants