# Spatial Control of Bone Remodeling by Gap Junction-Communicated cAMP

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $345,502

## Abstract

PROJECT SUMMARY
Numerous studies show that connexin43 gap junctions play a critical, albeit complex, role in the achievement of peak
bone mass, maintenance of bone quality, and the response to the bone anabolic effects of intermittent parathyroid
hormone and mechanical load. The skeletal effects of connexin43 deletions differ based on age, loading, disuse, and
even anatomical location. This complexity has challenged the dogma regarding the function of connexin43 in bone in
certain contexts. While biophysical data have shown that second messengers of varying molecular mass can pass
through connexin43 channels, we have little insight into the which messengers are biologically relevant, their
biological consequences, and the range or directionality with which these signals propagate between osteocytes and
osteoblasts. These issues are fundamentally important to unravelling the seemingly paradoxical findings for
connexin43’s functions in bone and to understand bone homeostasis. Supported by new and published data and using
cAMP as a model second messenger, our goal is to test the idea that signals, which arise in a subset of responsive bone
cells, are then distributed by connexin43 across distances to the appropriate effector cells to coordinate tissue
remodeling. In the absence of connexin43, this asymmetrical response to the stimuli and inability to share it results in
unintended partitioning of signals in a subset of cells, disrupting the physiological function. These events, in turn,
result in hyper-signaling in the responding cells and the absence of signaling in neighboring populations. This
uncouples coordinated bone remodeling and leads to low bone quality. This model of signal partitioning could explain
these seemingly paradoxical findings for connexin43 deficiency in cortical bone basally and in response to load. We
will test the central hypothesis that intercellular communication of cAMP through connexin43 acts as a molecular
ruler, spatially defining bone remodeling. Thus, the ability of connexin43 to permit long-distance translation of
biological signals between cells defines the distance from a source that coordinated bone remodeling occurs. We will
examine this hypothesis in two aims. The first will examine how connexin43 communicated cAMP spatially regulates
osteoblast and osteocyte activity and cortical bone remodeling. The second will examine the molecular consequence
of connexin43-communicated cAMP on the magnitude and/or sensitivity of the cortical bone mechano-response. Our
exciting preliminary data show that cAMP primes the response of osteocytes to mechanical cues, at least in part, by
modulating the sensitivity of a TRPV4-dependent mechano-transduction pathway. In total, these studies will address
fundamentally important questions about the signals being transmitted by bone cells, the range and consequence with
which their communication impacts bone remodeling and will help to explain the paradoxical impacts of connexin43
on b...

## Key facts

- **NIH application ID:** 9893064
- **Project number:** 2R01AR063631-06A1
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Joseph P. Stains
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,502
- **Award type:** 2
- **Project period:** 2013-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893064

## Citation

> US National Institutes of Health, RePORTER application 9893064, Spatial Control of Bone Remodeling by Gap Junction-Communicated cAMP (2R01AR063631-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9893064. Licensed CC0.

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