# Endocrine Actions of Sclerostin

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2024 · —

## 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. Our previous studies suggest that sclerostin, an osteocyte-secreted factor that inhibits Wnt
signaling in bone, influences body composition and glucose homeostasis by augmenting adipocyte
differentiation. Preliminary studies suggest that sclerostin may exert its effect on adipose tissue in vivo by
modulating the sensitivity of adipocytes to -adrenergic signals that stimulate adipose tissue browning. In
this renewal application, we will utilize a combination of genetic and pharmacological approaches to explore
the interaction between endocrine sclerostin and -adrenergic signaling. Our hypothesis predicts that
sclerostin deficiency leads to adipose tissue browning due to an increase in -adrenergic sensitivity; and
the loss of negative feedback inhibition since sclerostin gene expression appears to be responsive to
thermogenic signaling. Our approach will expand our understanding of the physiologic functions of
sclerostin; and help to determine if sclerostin neutralization, now approved for the treatment of
osteopenia/osteoporosis, can be leveraged to treat metabolic disorders like obesity and diabetes. 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:** 10768595
- **Project number:** 5I01BX003724-07
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** Ryan C Riddle
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768595

## Citation

> US National Institutes of Health, RePORTER application 10768595, Endocrine Actions of Sclerostin (5I01BX003724-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10768595. Licensed CC0.

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