# Control of Bone Mass by Progranulin

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2022 · —

## Abstract

The maintenance of healthy bones in adults requires coordinated bone turnover where bone formation is
closely coupled to bone resorption, allowing bone renewal with the maintenance of bone mass. Uncoupling
of bone formation and bone resorption underlies the loss of bone mass seen in a variety of conditions
including aging, the menopause, and various inflammatory disorders such as rheumatoid arthritis (RA).
These disorders are generally associated with enhanced bone resorption accompanied by rates of bone
formation that are inadequate for the level of resorption. Anti-resorptive therapies have been the traditional
approach for treating patients with low bone mass in these conditions, but it is increasingly recognized that
anabolic therapies that enhance bone formation constitute an important alternative strategy. Previous
studies have identified that inhibitory G protein (Gi) signaling in osteoblast lineage cells suppresses bone
formation and is an important driver of age-related bone loss in females, but the factors that are upstream
of this signaling pathway are unknown. Suppression of canonical Wnt signaling in osteoblast lineage cells
is also linked to reduced bone formation. The present study will use a variety of mouse models to test the
hypothesis that progranulin (PGRN), an inflammation-associated factor produced by macrophages and
implicated in age-related bone loss, is a critical upstream regulator of inflammatory cytokine production
and that PGRN-mediated cytokine production promotes bone loss through activation of Gi signaling and
suppression of canonical Wnt signaling in osteoblast lineage cells. This hypothesis will be tested in three
specific aims. In Specific Aim 1, the role of PGRN in bone marrow macrophage (BMM)-regulated bone
formation will be explored. To accomplish this, we will determine whether alternations in the population of
BMMs accounts for promotion of bone resorption by PGRN; whether expression of PGRN reduces the pro-
osteogenic activity of BMMs; and whether transplantation of BMMs from PGRN-deficient mice can protect
or reverse bone loss in adult female mice. Specific Aim 2 will address the role of suppression of anabolic
signaling pathways in the negative effects of PGRN on bone formation. The role of the canonical Wnt
pathway will be investigated in vivo in mice with targeted deletion of Ctnnb1, the gene encoding b-catenin,
and will be investigated in vitro in osteoblast lineage cells lacking expression of PGRN. The ability of PGRN
to inhibit Gs/cyclic AMP signaling will be assessed in vitro in cultured osteocytes and in vivo in its ability to
limit the anabolic response to intermittent PTH administration. Specific Aim 3 is a translational aim in which
we will explore the role of PGRN in mediating bone loss in two disorders associated with inflammation-
rheumatoid arthritis (RA) and estrogen deficiency-induced osteoporosis. We will determine whether PGRN
deficient mice are protected from bone loss after ovariectom...

## Key facts

- **NIH application ID:** 10368564
- **Project number:** 2I01BX003212-05A1
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** Robert Nissenson
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2016-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368564

## Citation

> US National Institutes of Health, RePORTER application 10368564, Control of Bone Mass by Progranulin (2I01BX003212-05A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10368564. Licensed CC0.

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