Bone Abstracts (2013) 1 PP174 | DOI: 10.1530/boneabs.1.PP174

Elevated levels of serotonin decrease bone volume by direct effects on bone turnover in rats

Igor Erjavec1, Tatjana Bordukalo-Niksic1, Jelena Brkljacic1, Martina Pauk1, Lovorka Grgurevic1, David D Thompson2, Vishwas M Paralkar2, Lipa Cicin-Sain3, Slobodan Vukicevic1, Gordana Mokrovic2, Maja Kesic2 & Danka Grcevic2

1Laboratory of Mineralized Tissues, School of Medicine, Center for Translational and Clinical Research, University of Zagreb, Zagreb, Croatia; 2Karos Pharmaceuticals, New Haven, Connecticut, USA; 3Laboratory for Neurochemistry and Molecular Neurobiology, Molecular Biology Department, Rudjer Boskovic Institute, Zagreb, Croatia.

Elevated levels of circulating serotonin have been reported to decrease bone mineral density1. Conversely, reduced serotonin (5HT) in mice lacking TPH1, the rate limiting enzyme for 5HT synthesis, was reported to be anabolic to the skeleton with high osteoblastic activity2. However, in other studies TPH1 deletion led to either an initial increase in BMD due to inhibition of osteoclastic bone resorption3, or had no bone effect4.

To address this issue, we used selective breeding to identify rats with elevated (high-5HT) and low (low-5HT) levels of platelet 5HT and high and low levels of platelet 5HT transporter activity. In high-5HT animals platelet serotonin levels and uptake were about 100% higher than in animals with low 5HT. Skeleton was analyzed with μCT, DEXA, histomorphometry and in vitro methods to evaluate the effects of high and low levels of serotonin on bone tissue.

In high-5HT rats, bone volume was significantly decreased due to increased bone turnover and an enhanced osteoclastogenesis paralleled by increased serum CTX and osteocalcin values. PTH, 1,25(OH)2D3, insulin, estrogen, FGF23, BMP6, and leptin were similar in the plasma of both groups. Cultured primary osteoblasts and osteoclasts from high-5HT and low-5HT rats produced 5HT and 5HT receptors that can locally regulate bone turnover. These results suggest that systemically elevated 5HT increased bone turnover leading to bone loss. Further research is required to delineate the 5HT role in the skeleton and to determine the role of serotonin on bone metabolism.

References: 1. Modder et al. J Bone Miner Res 25 415–422, 2010.

2. Yadav et al. Cell 135 825–837, 2008

3. Chabbi-Achengli et al. PNAS 109 2567–2572, 2012.

4. Cui et al. Nat Med 17 684–691, 2011.