# Role and Mechanism of Claudin-11 Action and Signaling in Bone

> **NIH NIH R01** · LOMA LINDA VETERANS ASSN RESEARCH & EDUC · 2023 · $322,300

## Abstract

Project Summary/Abstract
 Osteoporosis is a significant public health problem in the U.S. and poses a substantial financial burden. The
pathogenesis of osteoporosis is known to involve increased destruction of bone, not compensated by parallel
increases in the synthesis of new tissue. The only approved anabolic drug for osteoporosis, PTH, also
increases bone resorption, thereby limiting its long term use. Thus, there is an urgent need for development of
novel anabolic therapies for the treatment of osteoporosis. In our effort to identify control molecules and their
signaling pathways that contribute to the regulation of osteogenesis, we have discovered a novel role for the
Claudin (Cldn) family of tight junction proteins. In this RO1 application, our focus is on elucidating the role and
mechanism of action of Cldn11 in regulating functions of osteoblasts (OBs) based on our exciting new data
that mice with targeted disruption of the Cldn11 gene exhibit a severe deficit in trabecular bone volume (40%).
Additionally, Cldn11 expression is increased several-fold during fracture healing. While the traditional role of
Cldns is to regulate paracellular transport of small molecules, we have new exciting preliminary data that
suggests that Cldn11 acts on OBs non-canonically via interacting with a transmembrane protein, Tetraspanin3
(Tspan3), to regulate ADAM10-mediated Notch signaling. We will test this model of Cldn11 action as follows:
1) To test the hypothesis that the Cldn11 expressed in OBs regulates trabecular bone formation, we will
characterize the skeletal phenotype of OB-specific Cldn11 transgenic (Tg) mice by micro-CT, histology,
mechanical testing and gene expression and determine if the reduced bone formation in Cldn11 KO mice can
be rescued by transgenic expression of Cldn11 in OBs. 2) To test the hypothesis that Cldn11 effects on OBs
are mediated via its interaction with Tspan3, we will determine the functional consequence of Cldn11/Tspan3
interactions by evaluating if knockdown of Tspan3 abolishes Cldn11-mediated differentiation in OBs, in vitro
and in vivo. 3) To test the hypothesis that Cldn11/Tspan3 effects on OBs are mediated via ADAM10-mediated
regulation of Notch signaling, we will evaluate the consequence of disruption of the Cldn11/Tspan3 interaction
on ADAM10 maturation and activity via overexpression of a dominant negative mutant Cldn11 encoding the
Tspan3 binding domain and determine if the Cldn11/Tspan3 interaction regulates Notch signaling and OB
differentiation via modulation of ADAM10 activity. 4) To test the hypothesis that Cldn11 promotes fracture
healing via regulating Notch signaling, we will determine the fracture phenotype in Cldn11 Tg and/or Tspan3
KO and control mice using a stabilized closed femoral fracture model. We will use notch signaling reporter
mice to evaluate if Notch signaling is activated at the fracture site in the Cldn11 Tg mice and determine if
treatment with an ADAM10 inhibitor blocks activated Notch s...

## Key facts

- **NIH application ID:** 10678629
- **Project number:** 5R01AR070806-05
- **Recipient organization:** LOMA LINDA VETERANS ASSN RESEARCH & EDUC
- **Principal Investigator:** SUBBURAMAN MOHAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $322,300
- **Award type:** 5
- **Project period:** 2017-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10678629

## Citation

> US National Institutes of Health, RePORTER application 10678629, Role and Mechanism of Claudin-11 Action and Signaling in Bone (5R01AR070806-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10678629. Licensed CC0.

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