Biglycan Regulation of Regional Tendon Development Via the Pericellular Matrix

Tendons are a unique orthopaedic tissue that rely on a highly ordered tissue matrix for proper function. Tendon disease degrades this matrix order, causing deviations in resident cell behavior that result in decreased tissue function. Treatments for tendon disease remain ineffective due to a knowledge gap in the factors most vital for maintaining tendon health. Many matrix molecules help regulate tendon growth and maintenance, including biglycan and collagen VI. These molecules are attributed to the pericellular matrix, a critical matrix structure that preserves cellular health across multiple contexts. The role of the PCM, and how interactions between biglycan and collagen VI govern tendon health, however, remain unknown. This dissertation defined the coordinate roles of biglycan and collagen VI and determined that while both molecules are key for tendon health, collagen VI is a more robust regulator, and that biglycan and collagen VI do not play additive roles in tendon. This work sought to further refine biglycan’s regulatory mechanism in tendon by leveraging a unique model system of distinct tendon matrix environments—“wrap-around” tendons. In addition to the characteristic, aligned tendon matrix, wrap-around tendons contain a matrix that more closely mimics fibrocartilage. This work analyzed the effect of biglycan knockout across these distinct tissue contexts to determine the molecular mechanism by which biglycan regulates tendon function. In doing so, we mapped the postnatal development of regional tendon properties for the first time in mice. Results from this work demonstrate that while biglycan may regulated tendon function through the PCM, this mechanism is likely independent of collagen VI interactions. Instead, biglycan may regulate tendon properties by directly organizing the collagen matrix. Overall, this work provides unique insight into the role of biglycan across distinct tendon matrix environments and lays the foundation for future work that may identify the factors most essential for preserving tendon health. Such knowledge is critical for the prevention and treatment of tendon disease