# Rspondin-Lgr Axis in Bone Regeneration

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $400,079

## Abstract

Our funded grant, R01DE030716, ”Rspondin-Lgr Axis in Bone Regeneration”, is focused on examining the role
of Rspo2-Lgr6 signaling in calvarial regeneration. While there are some similarities in healing processes that
exist between long bones and bones of the skull, there are also important differences. As an example, the
calvaria heals exclusively through an intramembranous process while long bones heal through both
intramembranous and endochondral bone formation. An additional important difference that exists between
calvarial and long bone healing is the source and type of progenitor cell that contributes to bone healing. In
long bones, a critical aspect of the bone healing process begins with the expansion of mesenchymal
progenitors from the marrow and periosteum, which occurs immediately after injury. These cells then become
bone forming osteoblasts and chondrocytes. However, mechanisms that control long-bone skeletal
progenitor/stem cell activation, expansion, and differentiation in response to injury are poorly described. This
supplement will study the role of the R-spondin (ligand) – Lgr (receptor) signaling axis in regulating long bone
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 long-bone fracture healing has never
been examined, due to the lack of appropriate models. Our primary goal is to define the requirement of
Rspo2/3 and Lgr6 in mesenchymal progenitors in response to femoral fracture. We have defined two 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 long-bone mesenchymal progenitors at the
time of fracture. We will assess in vivo proliferation, Wnt signaling, and osteogenesis of progenitors, and
analyze healing by using µCT, histology, and mechanical testing. In Aim 2, Lgr6 knockout mice will be
investigated for their bone healing properties using parameters similarly to Aim 1. Completion of this project will
identify the requirement of Rspo2/3-Lgr6 interaction in long-bone fracture healing and will provide new
mechanistic insights into the action of cWnt signaling in bone healing that can be directly compared to similar
experiments conducted with calvarial healing in the parent grant.

## Key facts

- **NIH application ID:** 10261766
- **Project number:** 3R01DE030716-01S1
- **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:** $400,079
- **Award type:** 3
- **Project period:** 2020-09-18 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10261766

## Citation

> US National Institutes of Health, RePORTER application 10261766, Rspondin-Lgr Axis in Bone Regeneration (3R01DE030716-01S1). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10261766. Licensed CC0.

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