Elevated blood serotonin decreases bone volume via a mechanism involving insulin and calcitriol

To further characterize the role of serotonin (5HT) in bone metabolism, Wistar-Zagreb rat model consisting of the high-5HT and low-5HT subline with different platelet 5HT content and transporter (5HTT) activity has been used. Primary osteoclasts from the high-5HT subline had an increased expression of 5HTT, 5HT–2A receptor, Trap and cathepsin K, while osteoblasts showed no difference in the expression of 5HT elements or osteoblastic markers. However, upon addition of 5HT and insulin combination, expression of Alph and osteocalcin in osteoblasts was significantly upregulated. In 8 weeks old rats the bone volume of distal femur and lumbar spine was significantly decreased in high-5HT rats. Histomorphometric analysis revealed increased osteoblast activity in these animals, while no change in the number of bone cells was observed. Serum CTX value was significantly increased in high-5HT animals while no change in the osteocalcin level was detected. 5HT level had no effect on the PTH value, but calcitriol and FGF23 were decreased in high-5HT rats. Treatment with calcitriol reduced the platelet 5HT content by 20% in high-5HT rats while PTH had no effect on platelet 5HT content. High-5HT rats had a higher level of blood glucose and insulin, resulting in ahigher body mass as compared to low-5HT rats. A single streptozotocin injection lowered the insulin plasma value with a consequent decrease in the platelet 5HT by 20%. Treatment with fluvoxamine, a 5HTT inhibitor, reduced the 5HT level in both sublines by 50% that was accompanied by decreased insulin in plasma of low-5HT rats. These results demonstrate that 5HT affects the bone volume via a complex autocrine/paracrine and endocrine mechanism involving insulin and calcitriol. Thus, 5HT is not a single mediator of bone metabolism, but influences the bone volume via a complex biochemical network of hormones and growth factors associated with 5HT homeostasis.