The cell surface receptor, low-density lipoprotein receptorrelated protein 5 (LRP5) is a key regulator of bone mass. Lossof-function mutations in LRP5 cause the human skeletal disease osteoporosis-pseudoglioma syndrome, an autosomal recessive disorder characterized by severely reduced bone mass and strength. We investigated the role of LRP5 on bone strength using mice engineered with a loss-of-function mutation in the gene. We then tested whether the osteogenic response to mechanical loading was affected by the loss of Lrp5 signaling. In addition to studies in humans, mice have been created with loss-of-function mutations in the mouse ortholog of LRP5, called Lrp5 (9 -11). These mice recapitulate the clinical features observed in OPPG patients, suggesting that the mouse is a useful animal model for delineating the role of Lrp5 in the mammalian skeleton (9 -11). Additionally, transgenic mice that overexpress wild-type Lrp5 or a high bone mass causing missense allele of LRP5 (G171V) under control of the type I collagen promoter, have increased bone mass and skeletal strength (12). Taken together, these data indicate that LRP5 has an important role in determining skeletal mass, strength, and function.
Lrp5-null (Lrp5Although loss-of-function mutations in LRP5 impart clear deficiencies on the skeleton, it is unclear how LRP5 participates in the modulation of bone mass. The striking similarity between * This work was supported by National Institutes of Health Grants AR046530 (to C. H. T.) and AR053237 (to A. G. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Selective serotonin-reuptake inhibitors (SSRIs) antagonize the serotonin (5-hydroxytryptamine) transporter (5-HTT), and are frequently prescribed to children and adolescents to treat depression. However, recent findings of functional serotonergic pathways in bone cells and preliminary clinical evidence demonstrating detrimental effects of SSRIs on bone growth have raised questions regarding the effects of these drugs on the growing skeleton. The current work investigated the impact of 5-HTT inhibition on the skeleton in: 1) mice with a null mutation in the gene encoding for the 5-HTT; and 2) growing mice treated with a SSRI. In both models, 5-HTT inhibition had significant detrimental effects on bone mineral accrual. 5-HTT null mutant mice had a consistent skeletal phenotype of reduced mass, altered architecture, and inferior mechanical properties, whereas bone mineral accrual was impaired in growing mice treated with a SSRI. These phenotypes resulted from a reduction in bone formation without an increase in bone resorption and were not influenced by effects on skeletal mechanosensitivity or serum biochemistries. These findings indicate a role for the 5-HTT in the regulation of bone accrual in the growing skeleton and point to a need for further research into the prescription of SSRIs to children and adolescents.
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