Dr. Michael Albro

Spatiotemporal Activity of Mechanobiologically Activated TGF-b in the Synovial Joint

ABSTRACT:

The health of the synovial joint is dependent on the coordinated activity of specialized cells—notably, chondrocytes to maintain the integrity of the articular cartilage extracellular matrix (ECM) and joint-lining synovial fibroblasts to secrete biolubricants. TGF-b is a prominent anabolic signaling molecule in the synovial joint, present as an inactive latent complex, which must first undergo activation in order to elicit a cellular response. Recent work has uncovered intriguing physiologic mechanochemical mechanisms that promote latent TGF-b activation in the synovial joint, such as activation via physiologic shearing of synovial fluid or via deformation of the cartilage ECM. These mechanisms point to the existence of powerful mechanobiological feedback cascades, whereby TGF-b-mediated biosynthetic activity can be triggered during physical joint activity (e.g., walking, exercise), thus acting to maintain synovial joint health. However, the impact of mechanobiological TGF-b activation pathways on synovial joint biosynthesis is complex, influenced by multiple pools of latent TGF-b in different joint tissue regions (synovial fluid versus cartilage ECM) and a complex array of chemical reactions that act on the activated TGF-b molecule. In this work, we implement computational and experimental models to better understand the role of mechanochemical-activated TGF-β in regulating the functional biosynthetic activities of synovial joint cells. Reaction-diffusion models describe the pronounced role of chemical reactions in modulating the complex spatiotemporal activity of TGF-b in the joint—notably, 1) different pools of activated TGF-b undergo a spatial sequestration in the ECM to act on different tissue regions, and 2) short durations of physiologic activity (< 1 hour) can provide long term (> 24 hours) TGF-b exposure to synovial joint cells.  Ex vivo tissue models subsequently demonstrate the role of this mechanobiologically activated TGF-b on regulating specific functional biosynthetic activities in synovial joint tissues, including maintaining the composition and mechanical properties of the cartilage ECM and enhancing the secretion of biolubricants. Lastly, we use modeling frameworks to explore the influence of aberrant activation of latent TGF-b during osteoarthritis on the induction of joint pathology and discuss how modeling frameworks can be used in the future to guide the development of TGF-b modifying therapies to treat synovial joint degeneration.

NARRATIVE BIOSKETCH:

Prof. Michael Albro currently serves as Assistant Professor of Mechanical Engineering at Boston University (BU) with affiliations in the Department of Biomedical Engineering, Division of Material Science & Engineering, and Photonics Center. His orthopaedics research group incorporates disciplines of biomechanics, mechanobiology, tissue engineering, and spectroscopy in order to: 1) understand the pathophysiology of synovial joint degenerative disorders, 2) develop novel diagnostic modalities, and 3) advance novel treatments into the clinic. Prof. Albro received his Ph.D. from Columbia University and served as a Marie Curie International Fellow in the Stevens Group at Imperial College London. His research has been funded by the National Institutes of Health, National Science Foundation, Musculoskeletal Transplant Foundation, and Arthritis Foundation to support projects on cartilage tissue engineering, orthopaedic growth factor mechanobiology, and Raman spectroscopic diagnostics of osteoarthritis. He recently received the Dr. James R. Neff Research Award from MTF Biologics, and the Dean’s Catalyst Award and Material Science & Engineering Innovation Award from Boston University.