# CaMKK2 Signaling in Osteoarthritis

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $313,889

## Abstract

PROJECT SUMMARY/ABSTRACT
Osteoarthritis is a highly debilitating disease affecting more than a quarter million people worldwide. Its
etiology is multifactorial, with age, gender, obesity, joint injury and heredity among the contributing factors.
Articular cartilage is intrinsically unable to heal itself. Any damage results in its progressive loss, inflammation
and pain. OA is a disease of the entire joint, and its pathology includes the progressive loss of cartilage,
subchondral bone thickening, osteophyte formation, synovial inflammation, degeneration of ligaments and
knee menisci, and hypertrophy of the joint capsule. Molecular mechanisms regulating OA are poorly
understood. No effective disease-modifying treatments are currently available for OA, leaving pain
management or surgical joint replacement as the only therapeutic options. Our preliminary studies identify
Ca2+/CaM-dependent kinase kinase 2 (CaMKK2) as a potential therapeutic target against OA. Articular
chondrocytes express CaMKK2 and its levels are higher in OA. Genetic ablation or pharmacological inhibition
of CaMKK2 protects against cartilage degradation, synovial inflammation, and subchondral bone alterations in
a murine model of surgically induced OA. When challenged with interleukin-1β, articular chondrocytes from
Camkk2-/- mice display attenuated catabolic and inflammatory responses, in part through downregulation of the
adenosine mono-phosphate dependent protein kinase and p38 mitogen activated protein kinase signaling
pathways. Based on these data, we hypothesize that CaMKK2 coordinates chondrocyte-responses to injury
and inflammatory cytokines, and its function in chondrocytes plays a crucial role in the development of OA.
Aim 1 will investigate whether the protection from OA as observed in the global knockout mice comes from the
cell-intrinsic role of CaMKK2 in chondrocytes. Aim 2 will elucidate the mechanisms by which CaMKK2
regulates catabolic and inflammatory responses in chondrocytes. Further, absence or inhibition of CaMKK2
suppresses macrophages and osteoclasts. Conditional deletion of CaMKK2 from these cells, as proposed in
Aim 3, will provide insights on how CaMKK2 function in synovial macrophages and subchondral bone
contribute to OA, and/or influence chondrocyte responses to inflammatory cytokines. Information generated
from the proposed studies will provide a basis for developing CaMKK2 inhibition as a novel therapeutic
approach to treat OA.

## Key facts

- **NIH application ID:** 10376643
- **Project number:** 3R01AR076477-02S1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Uma Sankar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $313,889
- **Award type:** 3
- **Project period:** 2020-03-13 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376643

## Citation

> US National Institutes of Health, RePORTER application 10376643, CaMKK2 Signaling in Osteoarthritis (3R01AR076477-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10376643. Licensed CC0.

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