# The role of osteoblast progenitors in response to bone anabolic agents

> **NIH NIH P50** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $647,103

## Abstract

Project Summary – Project 1
The goal of this project is to understand the effects of osteoporosis anabolic therapies on
osteoblast progenitors. This project aligns with the overall goal of the CORT in that skeletal
stem cells (including osteoblast progenitors) represent an important, yet poorly understood,
target of osteoporosis anabolic therapy. Specifically, this project will focus on determining why
the bone anabolic effect of romosozumab (anti-sclerostin antibody) wanes so quickly over time.
To accomplish this translational research goal, complementary approaches will be pursued
using patient and mouse samples. First, in Aim 1, in a prospective clinical study, we will obtain
bone-relevant bio-samples (trans-iliac crest core biopsies, bone marrow aspirates, and
peripheral blood) from post-menopausal women with osteoporosis during the course of
romosozumab therapy. These newly-collected samples will be analyzed along with bone
marrow samples previously obtained from post-menopausal women treated with teriparatide.
Therefore, we will compare and contrast the effects of these two distinct osteoporosis anabolic
agents. In this project, bone marrow aspirates will be analyzed by multi-color flow cytometry,
and non-hematopoietic stromal cells will be studied using a cocktail of antibodies that detects
surface-expressed antigens that sub-divide marrow stroma in order to define treatment effects
on human marrow stromal fractions. In addition, non-hematopoietic stromal cells will be
prospectively isolated for single cell RNA-sequencing. This analysis will afford unbiased
perspectives on the molecular heterogeneity of marrow stroma, effects of osteoporosis anabolic
treatments, and key information to explain the waning efficacy of romosozumab over time. To
complement these studies using human-derived samples, in Aim 2 we will combine lineage
tracing with single cell RNA-sequencing in mice to assess the effects of sclerostin antibody on
osteoblast precursors over time. Incorporating lineage tracing into our approach will prove that
putative progenitor populations become osteoblasts, and build confidence in cross-species,
conserved gene regulatory networks that are responsible the effects of osteoporosis anabolic
agents over time. Results from this project will be compared to comparable approaches in
Project 2 which focus on osteocytes. The Bioinformatics Core will play a crucial role in analysis
of cross-species single cell transcriptomic data. Ultimately, this merged analysis will generate
powerfully-informed, novel hypotheses regarding bone stem cell biology and responses to bone
anabolic agents.

## Key facts

- **NIH application ID:** 10757747
- **Project number:** 5P50AR080596-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** HENRY M. KRONENBERG
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $647,103
- **Award type:** 5
- **Project period:** 2023-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757747

## Citation

> US National Institutes of Health, RePORTER application 10757747, The role of osteoblast progenitors in response to bone anabolic agents (5P50AR080596-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10757747. Licensed CC0.

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