An Investigation of the Biophysical and Biochemical Properties of Perlecan/HSPG2: Implications for Bone Mechanotransduction and Endochondral Ossification
Martinez, Jerahme R
Stern, Michael; Farach-Carson, Mary Cindy
Doctor of Philosophy
Perlecan, also known as heparan sulfate proteoglycan 2 (HSPG2), is a very large secreted proteoglycan ubiquitously expressed in all basement membranes and in the territorial matrix of skeletal tissues. Perlecan is particularly important for the formation and stabilization of tissue layers and its absence is catastrophic for bone and cartilage development. In mineralized bone, perlecan is a key component of pericellular matrix (PCM) surrounding osteocytic processes that preserve fluid flow throughout bone tissue. In addition, recent findings have coupled perlecan expression, along the osteocyte cell surface, to bone mechano-adaptive response. Perlecan’s mechanical properties, important for maintaining the osteocyte cell-bone matrix interface, were studied for the first time. This work demonstrated perlecan functions as a semi-flexible tether that is capable of withstanding physiological loads imposed on cortical bone.The second part of this study examined perlecan in the context of early precartilage condensation. This study demonstrated a novel sub-domain of perlecan, PLN IV-3, located in its fourth domain modulates cell-matrix interactions that are involved in the chondrogenic process. When presented as part of the substratum, PLN IV-3 suppressed focal adhesion kinase (FAK) phosphorylation and signaling through the mitogen-activated protein kinase (MAPK) cascade. This led to reduced cell migration, increased cell-cell adhesion, and decreased cell proliferation, all of which are hallmarks for mesenchyme condensation and subsequent precartilage formation. I hypothesize that this is a possible mechanism by which perlecan functions to coordinate the migration of mesodermal cells and drive chondrocyte differentiation as seen during development. Together, these studies suggest perlecan possesses multifunctional properties that affect bone health throughout various stages of life.