ORF16-06 - Investigating Sclerostin and Low-Density Lipoprotein Receptor-Related Protein 5 Interactions in Adipose Tissue during Parathyroid Hormone-Mediated Bone Formation

Intermittent parathyroid hormone (iPTH) administration is indicated for the treatment of low bone mass and the prevention of fracture, but despite decades of work new mechanisms of action are still being uncovered. In our previous work, we demonstrated that PTH acts on white adipocytes to stimulate lipolysis and that the liberated fatty acids undergo beta-oxidation in osteoblasts to fuel bone formation. Since ablating the expression of the PTH receptor in adipocytes and inhibiting fatty acid oxidation in osteoblasts abolished iPTH-induced bone formation, we speculated that additional mechanisms of communication between adipose and osteoblasts coordinate this interaction. As a first step in our studies, we examined the lipolytic response to acute PTH treatment, while simultaneously examined bone-derived factors in the serum. Serum fatty acids and the levels of phosphorylated hormone sensitive lipase were significantly increased within 15 minutes of PTH treatment and remained elevated for 1 hour. However, serum fatty acid levels dropped below those of saline treated mice 3 and 6 hours after PTH treatment, suggestive of reesterification in adipose. Serum levels of sclerostin, a local inhibitor of bone formation and systemic regulator of body composition, were reduced 3 hours after PTH treatment. We hypothesized that sclerostin, through its interaction with low-density lipoprotein receptor-related protein 5 (Lrp5), regulate PTH signaling in adipose tissue to inhibit lipolysis during bone formation. Consistent with this hypothesis, Sost-/- mice release more fatty acids in response to acute PTH treatment than PTH-treated littermate controls, suggesting that the absence of circulating sclerostin creates a more permissive environment for PTH to stimulate lipolysis in adipocytes. Unexpectedly, Sost-/- exposed to a longer PTH treatment regimen have a smaller bone formation response compared to PTH-treated controls or saline-treated Sost-/- mice. We are currently investigating the potential desensitization to PTH signaling in both bone and adipose tissue in sclerostin-deficient mice. Additionally, mice that lack Lrp5 specifically in adipocytes (Lrp5fl/fl;AdipoQCre) also have an impaired bone-forming response to PTH over time. Taken together, these data suggest a role for sclerostin-Lrp5 interactions in adipose tissue that are important for iPTH-mediated bone formation.