# Bone neuro-mechanosignaling and inflammation: New players in diabetic osteopenia

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $418,836

## Abstract

Project Summary
 Bone loss is a diabetic complication that is often overlooked and the underlying mechanisms are still not
well understood. We have proposed that altered regulation of the osteocyte Panx1-P2X7R mechanosignaling
complex disrupts proper load-induced bone adaptation and likely contributes to bone loss in Type 1 diabetes
(T1D). However, load-induced regulation of bone mass occurs not only at the local bone level but remotely
involving direct signaling between the bone and the nervous system. Diabetes affects the nervous system,
particularly sensory nerves and yet, the extent to which diabetes impairs neural regulation of load-induced
bone responses is still unknown. Our studies indicate that besides its role in osteocytic mechanosignaling,
Panx1-P2X7R also participates in bone neuro-mechanosensory signaling and mediates load-induced
inflammasome activation, two new functions that are also targeted by diabetes. Reduction in neurotrophic
factors, mainly NGF, is a hallmark of diabetic peripheral neuropathy. NGF and its TrkA receptor are
components of the bone neuro-mechanosensory system. Load-induced NGF release from osteoblast has been
proposed to initiate NGF-TrkA signaling in bone sensory fibers that is essential for load-induced bone
formation in mice. Our preliminary data indicates that NGF-TrkA signaling is attenuated in T1D Akita bones, as
evidenced by lower NGF levels in bone and dorsal root ganglia (DRG) innervating the hind limbs. Moreover we
observed that loading regulates expression of NGF-TrkA signaling components, a response that is lost in T1D
bones. This finding suggests that diabetes disrupts the neurosensory axis of the bone mechanosensory
system, thereby impairing the neural component of the load-induced regulation of bone formation. In addition,
findings of load-induced Panx1-P2X7R upregulation in DRG suggest its participation in mechanisms that
modulate bone sensory neurons excitability. Inflammation is associated with bone loss. Inflammatory cytokines
are shown to be increased in bones at early stages of T1D in mice, which has been proposed to be necessary
for induction of diabetic bone loss. Our preliminary data indicates that loading worsens inflammation in T1D
Akita, which coincides with Panx1-P2X7R dysregulation and inflammasome activation. Load-induced flaring of
inflammation in diabetic bone is likely driven by Panx1-P2X7R, known activators of NLRP3 inflammasome.
Based on our preliminary data, we propose that (1) diabetic peripheral neuropathy contributes to the etiology of
diabetic osteopenia by affecting the bone sensory fibers and altering neural regulation of load-induced bone
formation; (2) Panx1-P2X7R regulation not only in the bone but also in the DRG is essential for load-induced
responses and skeletal adaptation, and (3) load-induced dysregulation of Panx1-P2X7R in diabetic bone
augments local inflammatory responses that contribute to impair bone anabolic responses. To test these
hypotheses we will us...

## Key facts

- **NIH application ID:** 9832178
- **Project number:** 5R01AR073475-04
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Mia M Thi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,836
- **Award type:** 5
- **Project period:** 2018-03-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9832178

## Citation

> US National Institutes of Health, RePORTER application 9832178, Bone neuro-mechanosignaling and inflammation: New players in diabetic osteopenia (5R01AR073475-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9832178. Licensed CC0.

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