# Role and Mechanism of Action of Ksr2, an Obesity and Type 2 Diabetes Gene, in Bone Metabolism

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

## Abstract

Abstract
 In an increasingly aging and obese population, type 2 diabetes (T2DM) and osteoporotic fractures are major public health
concerns. Affecting more than 1 in 3 adults in the United States, obesity is the most important risk factor for T2DM. It is
now well established that obesity and T2DM have effects on fracture risk, and fractures in T2DM are associated with greater
morbidity than in the general population. Although bone density is generally known to be increased in obese and T2DM
patients, the underpinning causes that contribute to increased fracture risk in T2DM/obese subjects remain to be established.
Therefore, understanding the interactions of obesity, T2DM and fracture is becoming a pressing need to reduce the societal
and individual costs of fracture. Our efforts to identify control molecules and their signaling pathways that delineate a link
between T2DM, osteoporosis and obesity led to the exciting discovery that targeted disruption of kinase suppressor of Ras
2 (Ksr2), an obesity and T2DM gene, led to a >2-fold increase in trabecular bone mass at the distal femur of 4-month-old
mice besides inducing obesity and T2DM. By contrast, disruption of a closely related Ksr1 gene had no significant effect
on bone or obese phenotypes. KSR1 and 2 were discovered as scaffolding proteins that orchestrate the assembly of Raf,
MEK and ERK in the canonical Ras-Raf-MAPKs pathway. While a central role for Ksr2 expressed in hypothalamus has
been implicated in the control of feeding behavior and energy balance and, thereby obesity, we have new exciting
preliminary data that suggest that KSR2 expressed in osteoblasts acts locally in a cell autonomous fashion to regulate its
functions. Based on our preliminary data and published data, we propose a novel hypothesis that KSR2 regulates osteoblast
differentiation and bone formation via regulating mTORC1 signaling and its downstream hypoxia signaling. In this
competitive renewal RO1 application, we will test this model of KSR2 action as follows: 1) To test the hypothesis that
KSR2 acts in a cell autonomous fashion to regulate trabecular bone formation, we will generate osteoblast-specific Ksr2
conditional knockout mice and characterize its skeletal phenotype by micro-CT, histology, mechanical testing and gene
expression. 2) To test the hypothesis that KSR2 effects on osteoblasts are mediated via its regulation of mTORC1 signaling,
we will determine the functional consequence of KSR2/mTORC1 pathway interactions by evaluating if knockdown of
Raptor in osteoblasts abolishes the increased anabolic functions of Ksr2 knockdown osteoblasts. 3) To test the hypothesis
that KSR2/mTORC1 effects on osteoblasts are mediated via HIF1α signaling, we will evaluate changes in hypoxia signaling
in osteoblasts with conditional disruption of Ksr2 and/or Raptor. We will also determine if disruption of Hif1α expression
in osteoblasts rescues the skeletal phenotype in osteoblast-specific Ksr2 conditional knockout mice. Succe...

## Key facts

- **NIH application ID:** 10541191
- **Project number:** 5R01AR048139-14
- **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:** 2003-08-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10541191

## Citation

> US National Institutes of Health, RePORTER application 10541191, Role and Mechanism of Action of Ksr2, an Obesity and Type 2 Diabetes Gene, in Bone Metabolism (5R01AR048139-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10541191. Licensed CC0.

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