# Rspondin-Lgr Axis in Bone Regeneration

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $416,032

## Abstract

There is an urgent clinical need to develop new therapeutics to promote bone regeneration. A
critical aspect of the bone healing process begins with the expansion of periosteal progenitors
that occurs immediately after injury and then the differentiation of these progenitors to bone
forming osteoblasts and chondrocytes, yet mechanisms that control skeletal progenitor/stem cell
activation, expansion, and differentiation in response to injury are poorly described. Our project
will study the role of the R-spondin (ligand) – Lgr (receptor) signaling axis in regulating these
progenitors and bone regeneration. R-spondins (roof plate specific spondin) are a family of four
secreted matricellular proteins (Rspo1-4) that bind to Leucine-rich repeat-containing G-protein
coupled receptors 4/5/6 (Lgrs). Rspo-Lgr interaction potentiate canonical Wnt pathway by
preventing the turnover of Wnt Frizzled receptors, and hence determines canonical Wnt
signaling levels. While canonical Wnt signaling is known to play an important role in bone
regeneration, very little research has explored positive modulators of Wnt signaling. In
particular, the requirement of Rspo-Lgr in the context of fracture healing has never been
examined due to lack of appropriate models. Our primary goal is to define the requirement of
Rspo2/3 and Lgr6 in mesenchymal progenitors in response to bone injury. We have defined
three specific aims to address this goal. In Aim1, we will use single and compound Rspo2 and
Rspo3 floxed mice crossed with an alphaSMACreERT2 mouse to disrupt the Rspo2/3 genes in
mesenchymal progenitors at the time of fracture. Bone healing will be assessed using microCT,
histology, molecular analysis, and mechanical testing. Alterations in canonical Wnt signaling
and osteogenic potential of Rspo2/3 deficient progenitors will be assessed. In Aim 2, Lgr6
knockout mice will be investigated for their bone healing properties using parameters similar to
Aim 1. In Aim 3, Rspo2 will be delivered to bone injury sites and the impact on BMP and Wnt
signaling, progenitor activation and differentiation, and bone healing assessed. Completion of
this project will identify the requirement of Rspo2/3-Lgr6 interaction in fracture healing and will
provide new therapeutic directions for enhancing bone healing.

## Key facts

- **NIH application ID:** 9984722
- **Project number:** 1R01DE030716-01
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Kurt David Hankenson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $416,032
- **Award type:** 1
- **Project period:** 2020-09-10 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984722

## Citation

> US National Institutes of Health, RePORTER application 9984722, Rspondin-Lgr Axis in Bone Regeneration (1R01DE030716-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9984722. Licensed CC0.

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