# Age-related Control of Bone Quality by Osteocyte TGF-beta Signaling

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $37,749

## Abstract

PROJECT SUMMARY/ABSTRACT
Bone strength relies on bone mass and bone quality. However, in over half of fracture cases in elderly
populations, deficits in bone mass are not implicated. In these cases, it is believed that components of bone
quality, including bone material properties and nanoscale material performance, degenerate with age.
 Cellular mechanisms controlling bone quantity are well defined, but mechanisms regulating bone quality
are less well understood. Transforming growth factor beta (TGFb) is one of the known regulators of bone quality
through its control of osteocyte-mediated perilacunar/canalicular remodeling (PLR). TGFb regulated expression
of MMP13 in osteocytes is a critical aspect of PLR allowing the active remodeling of the bone extracellular matrix
(ECM). Absence of this activity, as seen in mice with an osteocyte-specific disruption of TGFb signaling
(TbRIIocy-/-), results in decreased MMP13 expression, disruption to the osteocyte lacunar canalicular network
(LCN), and low bone toughness despite any significant loss in cortical bone mass. However, the extent to which
the loss of PLR contributes to age related bone fragility remains unstudied and represents a significant gap in
knowledge toward the regulation of bone quality with age.
 Previous studies reveal similarities between the material behavior of aged bone and that of bone with
impaired TGFb signaling. Both exhibit embrittlement, seen by a lack of extrinsic toughening mechanisms such
as crack deflection, as well as decreases to macroscale material properties. Both demonstrate a disorganization
of the LCN. Additionally, aged bone accumulates large amounts of non-enzymatic crosslinks to the bone ECM
in the form of Advanced Glycation End products (AGEs). These crosslinks have been proposed as a direct
molecular impairment responsible for bone embrittlement with age. Data from RNAseq shows significantly
decreased MMP expression in aged mouse bone, implying a lack of PLR in aged bone for the first time.
Collectively, these data suggest a causal link between PLR and the poor bone quality in both aged bone and
TGFb deficient bone. This proposal tests the causality between these two models of degenerated bone quality.
 This project will test the hypothesis that osteocyte PLR is sensitive to declining TGFb activity in bone with
age and that this contributes to declining BQ over a lifetime. Aim 1 will evaluate similarities between the biological
mechanisms controlling bone quality in aging and TbRIIocy-/- bone. Aim 2 will utilize synchrotron x-ray experiments
to confirm if nanoscale deformation mechanics in TbRIIocy-/- bone are conserved from studies on aging bone to
connect these models on the nanoscale. Aim 3 will attempt a rescue of age degenerated bone quality by limiting
the activity of the TGFb signaling inhibitor Smad7 specifically within osteocytes to revitalize PLR and bone quality
in aged mice. This study will investigate if osteocytes are the cellular players respons...

## Key facts

- **NIH application ID:** 10021392
- **Project number:** 5F31AG063402-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Charles August Schurman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,749
- **Award type:** 5
- **Project period:** 2019-09-11 → 2022-09-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10021392

## Citation

> US National Institutes of Health, RePORTER application 10021392, Age-related Control of Bone Quality by Osteocyte TGF-beta Signaling (5F31AG063402-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10021392. Licensed CC0.

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