# The Role of Proline Metabolism During Osteoblast Differentiation and Bone Formation

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $321,473

## Abstract

Project Summary:
Proline is a multifunctional imino acid with myriad uses in the cell. Aside from direct incorporation into protein,
proline can be metabolized via a process known as the proline cycle. Here, proline is oxidized by proline
oxidase (PRODH) to form D1-pyrroline-5-carboxylate (P5C). PRODH is a FAD+ dependent enzyme that
donates electrons to complex II of the mitorchondrial electron transport chain thus coupling proline oxidation to
ATP synthesis. P5C is converted back into proline by the NADH dependent enzyme pyrroline-5-carboxylate
reductase (PYCR) to provide reducing power for glycolysis and the pentose phosphate pathways. It is
unknown how osteoblasts obtain proline, how proline uptake is regulated, or if and when the proline cycle is
required during differentiation. Osteoblasts express a diverse array of membrane-tethered amino acid
transporters to facilitate proline uptake. We have identified the system A neutral amino acid transporter
SNAT2 (encoded by Slc38a2) as the most highly expressed putative proline transporter in osteoblasts. Our
preliminary data indicates WNT stimulates proline uptake through SNAT2 that is necessary for osteoblast
differentiation in vitro. Moreover, mice homozygous for a null allele of Slc38a2 (Slc38a2-/-) have defects in
endochondral ossification. In this proposal, we will 1) establish the necessity of proline uptake through
Slc38a2/SNAT2 to regulate osteoblast differentiation and bone formation in vivo, 2) determine how SNAT2
activity is regulated by WNT signaling and 3) elucidate the necessity of proline metabolism via the proline cycle
in differentiating osteoblasts. Our findings will have broad implications in bone development, maintenance of
bone mass, skeletal repair and regeneration.

## Key facts

- **NIH application ID:** 10440352
- **Project number:** 5R01AR076325-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Courtney Michael Karner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $321,473
- **Award type:** 5
- **Project period:** 2020-08-10 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440352

## Citation

> US National Institutes of Health, RePORTER application 10440352, The Role of Proline Metabolism During Osteoblast Differentiation and Bone Formation (5R01AR076325-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10440352. Licensed CC0.

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