Sclerostin-Lrp5 Interactions During PTH-mediated Bone Formation

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Bone formation by osteoblasts requires large amounts of energy to fuel the synthesis, deposition, and mineralization of new bone matrix. During periods of rapid bone formation following anabolic signals like intermittent parathyroid hormone (iPTH) the ability to obtain sufficient energy supply is of even greater importance. Recent work from our lab indicates that the catabolism of fatty acids liberated from white adipose tissue by lipolysis represents a major energy source for osteoblasts. In these studies, we interrogated mechanisms by which osteoblasts and adipocytes regulate the transfer of fatty acid molecules. We hypothesized that bone-derived sclerostin, an inhibitor of local bone formation that also acts on adipocytes, regulates iPTH-induced lipolysis in adipocytes to fuel bone formation. We treated sclerostin knockout ( Sost KO) mice and their wildtype littermates with a single injection of PTH or saline vehicle for 30 mins and assessed the immediate lipolytic response. Serum analysis revealed that Sost KO mice had a greater level of free fatty acids than vehicle-treated Sost KO mice or PTH-treated wildtype mice. To assess changes in bone mass accrual and lipid metabolism, Sost KO mice were treated with PTH or saline vehicle for 5 days per week, for 6 weeks. Micro-computed tomography (MicroCT) of the distal femur showed the expected increase in bone volume fraction in PTH-treated wildtype mice, compared to vehicle-treated mice. However, PTH-treated Sost KO mice had a smaller bone formation response than wildtype or vehicle-treated Sost KO mice, suggesting that Sost KO mice may become desensitized to PTH treatment over time, losing the ability to respond to this anabolic signal. Since sclerostin exerts its effects on target tissues by binding the low-density lipoprotein receptor-related protein 5 (Lrp5) and Lrp6, we also examined the requirement for Lrp5/6 receptors in adipocytes for iPTH-induced bone formation. After 6 weeks of PTH treatment, the bone formation response to PTH was dramatically reduced in mice lacking Lrp5 in adipocytes (Lrp5flox;AdipoQCre) when compared to control littermates. By contrast, mice lacking Lrp6 in adipocytes exhibited an anabolic response identical to that in control mice. Together, these data suggest a role for circulating sclerostin and Lrp5 signaling in adipocytes in the osteoanabolic response to iPTH. Ongoing studies, including the histological and protein analysis of adipose tissue and lipolytic enzymes, will further elucidate the coordination of bone and adipose tissue metabolism in response to increased osteoanabolic signals. Funding source: NIH DK099134 and AR077533 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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