# The role of Tmem263 in regulation of bone mass and strength

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $172,607

## Abstract

Our previous genome-wide association study identified 56 loci that were associated with bone mineral
density (BMD) and fracture risk in men and women. One locus on chromosome 12q23.3 harboring the gene
TMEM263 (Transmembrane protein 263) was strongly associated with hip BMD (p<9.6x10-10). TMEM263
encodes a multi-pass transmembrane protein of unknown family. To identify the role of this gene in bone
biology, we tested the SNP (rs1053051) associated with hip BMD in the TMEM263 gene for allele-specific
expression (ASE) differences using human femoral bone samples. We observed a unidirectional allelic
imbalance in mRNA expression for this SNP, suggesting that variation in ASE in TMEM263 may contribute to
variation in hip BMD. The mouse Tmem263 gene was highly expressed in skeletal tissue compared to non-
skeletal tissues, and osteoblasts and osteocytes expressed 6-fold higher mRNA levels of Tmem263 compared
to osteoclasts. Also, in an established osteoblast cell line, OB6, gene-silencing with shRNA specific for
Tmem263 revealed decreased expression of genes important for bone formation and increased expression of
genes related to bone resorption. We recently made osteoblast-specific Tmem263 KO mice. Preliminary data
show that these mice display broken bones and significantly lower whole body aBMD, BMC and trabecular
bone mass and compromised bone micro-architecture compared to WT mice. Therefore, we hypothesize that:
1) the Tmem263 gene plays an important role in the acquisition and maintenance of bone mass; 2) osteoblast-
specific deletion of Tmem263 in mice will lead to reduced bone mass and strength compared to controls; 3)
lower BMD and strength in KO mice will result from decreased proliferation, impaired differentiation and/or
diminished activity of osteoblasts. We will test these hypotheses in global and osteoblast-specific Tmem263
knockout mice and Tmem263 overexpressing Tg mice. We will measure areal BMD of whole body, femur and
spine by in-vivo DXA and determine volumetric BMD for cortical and trabecular bone in femur by in-vivo μCT.
Bone strength will be tested in femur by 3-point bending. Further, we will determine the molecular and cellular
mechanisms responsible for changes in bone phenotype by measuring serum markers of bone turnover,
quantifying expression of genes important in bone formation and resorption, and performing static and dynamic
bone histomorphometry. We will identify protein-protein interaction partners of Tmem263 using two
complementary proteomics techniques. We will also use RNA sequencing in KO and overexpressing
Tmem263 newborn pups to identify global gene expression changes. The proteomic and RNA sequencing
studies will identify specific pathways and networks involved in Tmem’s role in bone health. In summary, we
propose to use novel mouse models to understand the function of a unique gene product on bone and mineral
metabolism. Successful completion of the proposed studies could open a new area of bone biology and ...

## Key facts

- **NIH application ID:** 10401449
- **Project number:** 5R21AR079005-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Michael J Econs
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $172,607
- **Award type:** 5
- **Project period:** 2021-05-05 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401449

## Citation

> US National Institutes of Health, RePORTER application 10401449, The role of Tmem263 in regulation of bone mass and strength (5R21AR079005-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10401449. Licensed CC0.

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