# Role of Src Kinase in Mechanically-Induced Bone Formation

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $518,792

## Abstract

Project summary: We seek to understand the molecular mechanisms that direct bone formation and
resorption in response to mechanical loading. Pharmacologic manipulation of these mechanotransduction
(MTD) signaling processes in bone cells has therapeutic potential. We propose a novel strategy that
investigates signaling mechanisms that suppress the stimulatory effects of loading (rather than focusing
on signaling pathways that stimulate new bone formation). The fundamental goal is to manipulate MTD
pathways so that even modest levels of exercise can have outsized anabolic effects if mechanisms that
inhibit load-induced bone formation are pharmacologically suppressed. Osteocytes (OCY), the most
abundant cell type in bone, coordinate the response of bone to mechanical load. We propose that the
tyrosine kinase Src functions in OCY as a novel suppressor of load-induced bone formation. Global Src
null mice have high bone mass (HBM). This is due in part to Src-dependent defects in osteoclast-
mediated bone resorption. However, we risk missing an important role that tyrosine kinases may play in
the anabolic arm of skeletal MTD if we attribute the HBM phenotype of Src KO mice entirely to an
osteoclast defect in bone resorption. We suggest there is an additional underappreciated role for Src in
the osteoblast/osteocyte (OB/OCY) population that inhibits mechanically-induced anabolic signals.
Specifically, we propose that upon activation by mechanical stimuli, Src dissociates from integrins
(membrane mechanosensors) and translocates to the nucleus as part of a multi-protein complex with
Proline-rich Kinase-2 (Pyk2) and the methylated DNA binding protein Methyl-CpG Binding Domain
Protein-2 (MBD2), to regulate epigenetics of key bone genes. Thus, OCY may utilize a SrcPyk2-MBD2
“mechanosome” to promote or suppress anabolic or anti-catabolic bone genes by altering promoter-
associated CpG islands. We propose to experimentally dissect the molecular mechanisms through which
Src inhibits bone formation using in vivo and in vitro approaches with the long term goal of better
understanding the clinical and translational potential of Src inhibitors to enhance bone density and fracture
susceptibility. Three aims are proposed: Aim 1 will determine the effect of targeted Src deletion from
osteocytes on basal and load-induced bone formation and on disuse-induced bone loss in mice. Aim 2 will
determine the role of Src in epigenetic regulation of mechanically sensitive bone genes. Aim 3 will
determine the molecular interactions of Src in the cytoplasm and nucleus of osteoblasts and osteocytes
subjected to fluid shear stress in vitro using FRET-FLIM microscopy.

## Key facts

- **NIH application ID:** 9879623
- **Project number:** 5R01AR069029-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Fredrick M Pavalko
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $518,792
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879623

## Citation

> US National Institutes of Health, RePORTER application 9879623, Role of Src Kinase in Mechanically-Induced Bone Formation (5R01AR069029-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9879623. Licensed CC0.

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