# Connexin channels in transducing mechanical signals in bone

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $335,500

## Abstract

Project Summary
Mechanical loading experienced by skeletal tissues plays an important role in bone formation and remodeling.
Osteocytes are the most abundant bone cell type and the major mechanosensory cells of the bone. They
orchestrate bone remodeling from their location throughout bone matrix by coordinating osteoblastic formation
and osteoclastic resorption. Osteocytes are connected to neighboring osteocytes and other bone cells via gap
junction channels and to extracellular environments via hemichannels. Both types of channels are formed by
connexin (Cx) 43. The involvement of Cx43 in response to mechanical stimulation of bone tissue has been
shown in gene knockout models; however, the distinct functions of gap junction channels and hemichannels in
osteocytes, as well as the mechanism underlying the physiological roles of these channels during mechanical
loading remain largely unknown. To dissect the physiological roles of these two types of channels, we have
recently developed two transgenic mouse models expressing Cx43 dominant negative mutants predominantly
in osteocytes. We are also generating a Cx43 mutant gene knockin mouse model to complement our
transgenic models. These mutations impair osteocytic gap junction channels and/or hemichannels. In addition,
we have generated antibodies that specifically inhibit Cx43 hemichannels, but not gap junction channels.
Moreover, we have developed novel approaches that allow us to assess osteocytic hemichannel activity in situ.
Preliminary data show that impairment of Cx43 hemichannels attenuates the anabolic effect of mechanical
loading on the bone. We and others have also shown that osteocytic Cx43 hemichannels are opened by
mechanical stress, releasing small bone anabolic factors including prostaglandins in vitro. The objective is to
determine the specific mechanistic role of Cx43 hemichannels in mediating the anabolic effect of mechanical
loading on the skeletal tissues. Three specific aims are proposed: 1) To test the hypothesis that osteocytic
Cx43 hemichannels play a crucial role in mediating anabolic function of mechanical loading on skeletal tissue.
2) To test the hypothesis that osteocytic Cx43 hemichannels mediate anabolic function of mechanical loading
via PGE2 release, and activation of PGE2 and Wnt signaling. 3) To test the hypothesis that activation and
inactivation of Cx43 hemichannels are specifically regulated by integrin activation/cytoskeleton and MAPK
signaling, respectively. The proposed studies are expected to have a major positive impact by defining the
mechanical transduction mechanism and its regulation in bone tissue, constituting potential, significant
contributions toward the development of new therapeutic agents for the treatment of osteoporosis and bone
loss.

## Key facts

- **NIH application ID:** 9989795
- **Project number:** 5R01AR072020-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Jean X Jiang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,500
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989795

## Citation

> US National Institutes of Health, RePORTER application 9989795, Connexin channels in transducing mechanical signals in bone (5R01AR072020-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9989795. Licensed CC0.

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