# Endocrine Actions of Sclerostin

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2020 · —

## Abstract

The skeleton, populated by large numbers of osteoblasts and osteocytes, requires a constant supply of
energy-rich molecules to fuel the: synthesis, deposition, and mineralization of bone matrix during bone
modeling and remodeling. As a result, studies performed over the last decade have expanded our
understanding of the physiologic functions of bone beyond locomotion, mineral ion storage, and
protection of vital organs to now include the secretion of hormones that contribute to the regulation of
whole-body metabolism. Sclerostin, an osteocyte-secreted factor that inhibits Wnt signaling by
interacting with the low-density lipoprotein receptor-related protein 5 (Lrp5) and Lrp6 co-receptors, has
generally been viewed as a local inhibitor of bone formation. However, human data raises the
possibility that sclerostin also antagonizes Wnt signaling in distant tissues as circulating levels are
increased in conditions of metabolic dysfunction. Moreover, preliminary studies described in this
proposal demonstrate that sclerostin deficiency (Sost-/- mice) alters body composition and glucose
homeostasis, and that sclerostin treatment augments adipocyte differentiation. These data lead us to
hypothesize that sclerostin fulfills an endocrine function that allows bone to communicate with other
metabolically active tissues, and to contribute to the coordination of whole body metabolism.
In this application, we will utilize a combination of genetic and pharmacological approaches to explore
the impact of sclerostin on adipose tissue development and function. Our hypothesis predicts that
circulating sclerostin enhances fat accumulation by suppressing signaling downstream of the Wnt co-
receptor Lrp5 and that this function is facilitated by Lrp4, a putative sclerostin receptor. Our approach
will enable the identification of previously unanticipated functions of sclerostin. We firmly believe that
the information gained from our studies will improve understanding of how the metabolic activity of the
skeleton impacts global metabolic activity. Such information is expected to significantly improve the
diagnosis, management, treatment, and prevention of the related metabolic disturbances of diabetes
and bone disease in aging Veterans.

## Key facts

- **NIH application ID:** 9898240
- **Project number:** 5I01BX003724-04
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** Ryan C Riddle
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898240

## Citation

> US National Institutes of Health, RePORTER application 9898240, Endocrine Actions of Sclerostin (5I01BX003724-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9898240. Licensed CC0.

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