The Overexpression of BMP Type I Receptor ALK3 has a Protective Effect in Degenerative Disc Disease in a Mouse Model.

Abstract

Basic Science. The goal of this study was to investigate a novel therapeutic approach for treating degenerative disc disease (DDD) by enhancing anabolic signaling through ALK3 overexpression in the intervertebral disc, using a mouse tail compression model. Our previous data showed induction of BMP/Smad signaling in intervertebral disc tissue of DDD patients. The role of such induction is not fully understood, but previous literature indicates mostly protective effects of exogenous BMPs against DDD. ALK3 transgenic mice (ALK3TG) were crossed to tamoxifen-inducible Aggrecan-Cre (Acan-CreERt2) mice to assess the protective effect of tissue-specific ALK3 overexpression using a tail compression device in the caudal vertebrae to induce DDD. Cre+;ALK3TG (GOF, n=40) and Cre-;ALK3TG (Cre- control, n=40) mice were used. At 4 and 8 weeks, tails were harvested and analyzed with histomorphometry and micro-computed tomography. In the male cohort, GOF mice showed significantly greater proteoglycan content compared to Cre- controls at 4 and 8 weeks following tail compression. There was no difference proteoglycan content in the female compression cohort at either time point. In the male cohort, GOF mice trended towards having a larger disc area than Cre- controls at 4 weeks following tail compression, but no difference was observed at 8 weeks. In the female cohort, disc area was significantly larger in GOF mice compared to Cre- controls at 4 and 8 weeks following tail compression. Using a tail compression device to model DDD, we found that ALK3 overexpression in aggrecan-expressing disc cells enhanced BMP signaling and maintained higher proteoglycan content in male mice and increased disc area in female mice.