# Mechanisms of osteocyte mechano-signaling and sclerostin regulation

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $329,703

## Abstract

PROJECT SUMMARY
Osteoporosis and other diseases of skeletal fragility affect more than 200 million people worldwide and
contributes to ~9 million factures annually. Preventing bone loss and/or restoring lost bone mass in patients is
of vital importance to limiting the personal and economic impact of diseases of skeletal fragility. A key target in
the stimulation of new bone formation is the protein sclerostin, an antagonist of the Wnt/beta-catenin signaling
cascade, which is produced by bone embedded osteocytes. Numerous osteoanabolic cues, including
mechanical load, reduce expression of the sclerostin leading to “de-repression” of osteoblastogenesis and
stimulation of de novo bone formation. However, key mechanistic details of how osteocytes sense mechanical
load, transduce these load signals to biologic effectors, the identity of these biological effectors and how
sclerostin bioavailability is regulated are unclear. Our preliminary data have uncovered a number of novel
mediators of how osteocytes sense and respond to mechanical cues. Specifically, we show that microtubule-
dependent cytoskeletal stiffness regulates mechano-activated Ca2+ influx. Furthermore, we implicate TRPV4
as a major mechano-dependent Ca2+ influx pathway that drives Ca2+ dependent activation of
calcium/calmodulin-dependent kinase II (CamKII) to reduce sclerostin bioavailability in the osteocyte. In the
present grant, we will use in vitro, ex vivo and in vivo models to determine the contribution of MT density and
cytoskeletal crosslinking to osteocyte mechanosensing, define the contribution and mechanisms of osteocyte
TRPV4 channel opening in response to mechanical stress and elucidate the mechanisms by which FFSS-
dependent CamKII activation regulates sclerostin degradation and Sost gene transcription. This work will more
fully explain the biological regulation of sclerostin, will mechanistically link several gaps in the knowledge of
how osteocytes sense and respond to mechanical load, and will reveal novel targets to improve or preserve
bone mass in aging and disease.

## Key facts

- **NIH application ID:** 10129281
- **Project number:** 5R01AR071614-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Joseph P. Stains
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $329,703
- **Award type:** 5
- **Project period:** 2018-03-21 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129281

## Citation

> US National Institutes of Health, RePORTER application 10129281, Mechanisms of osteocyte mechano-signaling and sclerostin regulation (5R01AR071614-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10129281. Licensed CC0.

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