Divergent Temporal Expression of Hyaluronan Metabolizing Enzymes and Receptors with Craniotomy vs. Controlled-Cortical Impact Injury in Rat Brain: A Pilot Study

Abstract

Traumatic brain injury (TBI) triggers many secondary changes in tissue biology, which ultimately determine the extent of injury and clinical outcome. Hyaluronan [hyaluronic acid (HA)] is a protective cementing gel present in the intercellular spaces whose degradation has been reported as a causative factor in tissue damage. Yet little is known about the expression and activities of genes involved in HA catabolism after TBI. Young adult male Sprague-Dawley rats were assigned to three groups: naïve control, craniotomy, and controlled-cortical impact-induced TBI (CCI-TBI). Four animals per group were sacrificed at 4 h, 1, 3, and 7 days post-CCI. The mRNA expression of hyaluronan synthases (HAS1-3), hyaluronidases (enzymes for HA degradation, HYAL 1–4, and PH20), and CD44 and RHAMM (membrane receptors for HA signaling and removal) were determined using real-time PCR. Compared to the naïve controls, expression of HAS1 and HAS2 mRNA, but not HAS3 mRNA increased significantly following craniotomy alone and following CCI with differential kinetics. Expression of HAS2 mRNA increased significantly in the ipsilateral brain at 1 and 3 days post-CCI. HYAL1 mRNA expression also increased significantly in the craniotomy group and in the contralateral CCI at 1 and 3 days post-CCI. CD44 mRNA expression increased significantly in the ipsilateral CCI at 4 h, 1, 3, and 7 days post-CCI (up to 25-fold increase). These data suggest a dynamic regulation and role for HA metabolism in secondary responses to TBI.

White matter damage after traumatic brain injury: A role for damage associated molecular patterns

“…In line with these findings, gene expression for hyaluronan synthases (HAS1) and HAS2, which catalyze the production and extracellular release of hyaluronan, was increased in the ipsilateral brain at 1–3 days post-TBI [142]. Hyaluronidase 1 (HYAL1) also was increased in the contralateral hemisphere at 1–3 days post-TBI [142] whereas expression of the HA receptor, CD44, was dramatically increased around the contusion for up to one week post-TBI [142].…”

“…In line with these findings, gene expression for hyaluronan synthases (HAS1) and HAS2, which catalyze the production and extracellular release of hyaluronan, was increased in the ipsilateral brain at 1–3 days post-TBI [142]. Hyaluronidase 1 (HYAL1) also was increased in the contralateral hemisphere at 1–3 days post-TBI [142] whereas expression of the HA receptor, CD44, was dramatically increased around the contusion for up to one week post-TBI [142]. Moreover, a recent genome wide sequencing study from perilesional cortex, thalamus, and hippocampus at three months post-TBI separately revealed a similar upregulation of CD44 after TBI [131], suggesting a dynamic regulation and role for HA metabolism after TBI; however, the precise functions and therapeutic potential of HA remains poorly defined after CNS injury.…”

Comment on: PH20 is not expressed in murine CNS and oligodendrocyte precursor cells

“…PH20 was also reported to be present, albeit at low levels, in the rat brain in a study on traumatic brain injury 6. These studies found PH20 in the brain, under certain conditions, using both antibody‐based techniques and PCR.…”

Extracellular matrix and traumatic brain injury

“…Another role of HA in TBI pathophysiology is through the degradation of HA into small fragments by injury-associated reactive oxygen species (Soltes et al 2006) and activation of the HA degrading enzyme hyaluronidase (Xing et al 2014). Hyaluronan fragments are biologically active, and can modulate the immune response and promote angiogenesis (Stern et al 2006).…”