Hyaluronan (HA) is a polysaccharide that is present within the extracellular matrix (ECM) of many connective tissues, including tendon. HA provides structure and viscosity to the ECM, suggesting that it plays a passive role in connective tissues. Recent studies, however, have revealed a more active role for HA during wound healing, whereby it induces inflammatory gene expression through direct interaction with cell surface receptors. While wound healing in adult tissue is characterized by marked fibrosis, extensive experimental data has shown that fetuses in the early to mid-gestational age respond to injury in a fundamentally different manner, demonstrating no substantial inflammatory response or scarring, as well as a unique ECM profile. The mechanisms that underlie this distinctive fetal response to injury are unknown, however HA is thought to play a crucial role. The specific source and function of HA in wound healing remain poorly defined, but it is known that in the fetus, elevated levels of HA are present in skin wounds up to twenty one days post-injury, whereas in adult skin repair, HA levels peak at two to four days and then fall rapidly. Local removal of HA is a receptor-mediated event and the primary HA receptor, CD44, plays a key role. CD44/HA interactions have been implicated in multiple inflammatory events, including activation of the well-known pro-inflammatory cytokine, TGF-beta. Elucidation of the mechanisms by which HA influences healing outcome and understanding the contribution of the molecules involved may enable us to identify new targets for therapeutic intervention after tendon injury. Therefore, the overall aim of this bioengineering study is to examine the effect of HA/receptor interaction in healing tendon and to determine the role of key mediators in this process. The overall hypothesis is that HA/receptor interactions, primarily those mediated by CD44, are critical for initiation and amplification of the inflammatory cascade that characterizes tendon healing, and for the fibrosis that ensues.
The specific aims are to analyze the effects of universally blocking HA binding, specifically blocking CD44/HA binding, and specifically enhancing CD44/HA binding in injured patellar tendons by evaluating the inflammatory cell and cytokine response, the mechanical properties and the collagen fiber organization. ? ? ?
| Ansorge, Heather L; Beredjiklian, Pedro K; Soslowsky, Louis J (2009) CD44 deficiency improves healing tendon mechanics and increases matrix and cytokine expression in a mouse patellar tendon injury model. J Orthop Res 27:1386-91 |
