Mechanical forces play a role in skeletal joint development. Alterations in motion or mechanical forces at the joint can result in joint deformity or dysplasia. In this project we will examine the role of mechanical forces in joint development in the axolotl, a salamander capable of regenerating its limbs. Limb regeneration uses the same developmental processes as growth, but facilitates an environment in which the mechanical and biochemical environment can be manipulated during (re)growth. We will determine the role of 1) lack of motion; 2) altered motion, and 3) lack of cellular response to motion during limb growth. Computational models will be used to determine the mechanical and biochemical environment of the developing limb, to predict changes in shape of the joint, and to compare with experimental joint shapes. This research will help to elucidate the role of mechanical forces in joint development, the cellular signaling mechanisms that are involved in responding to the joint's mechanical environment, and how the mechanical environment can be manipulated to alter joint shape. The objective of our outreach component is to excite people about mechanobiology in the context of limb regeneration. We will tap into the rich Center for STEM Outreach at Northeastern, which aids in recruitment, logistics, and planning of outreach activities. For example, during the course of this project, we will train high school students through Northeastern's Young Scholar Program, which places high school students (often underrepresented minorities) into labs for summer research.
The novel animal model, the axolotl (Mexican salamander), will be used to explore how mechanical signals and cellular transduction of those signals regulate limb morphogenesis. It is theorized that cyclic hydrostatic stress influences biomolecular transport and osmotic stress influences ion channel signaling in cartilage. These mechanical factors play a critical role in transduction of the mechanical environment into a biological response. We will examine the effect of: limb denervation, tissue grafting resulting in a reverse flexing limb, and inhibition of ion signaling using gadolinium in the water during regeneration. Computational models of the experiments will be generated to determine mechanical stresses and biochemical diffusion gradients and simulate cartilage morphogenesis. This work will combine a tissue level finite element model with reaction/diffusion equations for biomolecular reactions, particularly the Ihh-PTHrP pathway that is critical to cartilage growth. By combining animal experiments with computational modeling the critical mechanical and biochemical signals (and their interaction) can be explored during joint morphogenesis.
