# Osteoblasts Role in Dysfunction of Body Adiposity and Bone Metabolism

> **NIH NIH R56** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $392,627

## Abstract

ABSTRACT: Patients with metabolic diseases, such as obesity, diabetes, and lipodystrophy exhibit altered
bone and fat mass, fat distribution, and energy homeostasis. The underlying mechanisms involved in these
dysregulations are poorly understood. Bone and fat tissue are both endocrine organs and secrete factors that
regulate energy metabolism. Bone synthesizing osteoblasts and fat forming adipocytes are derived from
common mesenchymal progenitors. Increased bone marrow fat and decreased bone mass is noted in
osteoporosis, diabetes, and aging. Osteoporotic bones at highest risk for a fracture always exhibit increased
marrow fat. These clinical observations suggest that targeting bone marrow fat may be a treatment for these
diseases and for 2-million fractures in US adults that occur yearly due to osteoporosis and low bone mass.
However, the origin and function of the bone marrow fat, as well as its relationship to the bone and other
peripheral fat depots are not very clear. The bone marrow fat is a unique fat depot that is located adjacent to
the bone and is different from either white or brown adipose tissue. In this study, we aim to identify molecular
mechanisms underlying the metabolic diseases with comorbidity of the bone and fat, especially novel factors
secreted by the osteoblast and osteocytes that can regulate marrow adipogenesis, peripheral fat distribution,
energy homeostasis and maintenance of adult bone mass.
The Runx2 transcription factor is essential for the commitment of mesenchymal progenitors to the cells of
skeletal lineage. Global null mice of the Runx2 gene are embryonic lethal due to complete loss of osteoblast
differentiation and bone formation. We have recently published that Runx2 is also essential for chondrocyte
proliferation, hypertrophic maturation, and endochondral ossification. Our preliminary data show that selective
deficiency of Runx2 in mature osteoblasts and osteocytes inhibits postnatal bone synthesis and trigger a rapid
onset of osteoporosis, premature aging, and death. Runx2 activity inhibits commitment of mesenchymal cells
to the adipocyte lineage. Deletion of Runx2 in osteoblasts/osteocytes results in the near absence of visceral
adiposity but a dramatic increase in marrow adipogenesis. We further demonstrate that Runx2 blocks
adipogenesis by altering energy metabolism and by inhibiting critical signaling from Akt and Erk in the insulin
pathways. Based on the preliminary data we hypothesize that Runx2 regulated signals from mature osteoblast
and osteocytes control marrow adipogenesis, peripheral fat distribution, and energy homeostasis. We will
utilize novel mouse models to test our hypotheses in three specific aims. Aim 1 will examine the role of Runx2
deficient osteoblasts and osteocytes in the reciprocal maintenance of adult fat and bone mass. Aim 2 will test
the requirement of osteoblast/osteocyte for marrow and peripheral adiposity, and Aim 3 will uncover molecular
signals and mechanisms for energy hom...

## Key facts

- **NIH application ID:** 10255860
- **Project number:** 1R56AG065129-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Amjad Javed
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $392,627
- **Award type:** 1
- **Project period:** 2020-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10255860

## Citation

> US National Institutes of Health, RePORTER application 10255860, Osteoblasts Role in Dysfunction of Body Adiposity and Bone Metabolism (1R56AG065129-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10255860. Licensed CC0.

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