# Contribution of Osteocytes to the Musculoskeletal Effects of Multiple Myeloma

> **NIH NIH R01** · UNIV OF ARKANSAS FOR MED SCIS · 2021 · $409,850

## Abstract

Contribution of Osteocytes to the Musculoskeletal Effects of Multiple Myeloma
MPI: Roodman and Bellido
7. Abstract
Osteolytic cancer in bone (OCIB) occurs frequently in cancer patients and is a major contributor to decreased
survival and quality of life. Pathologic fractures caused by OCIB in multiple myeloma (MM) increases their risk
of death >20% compared to patients without fractures. In addition, OCIB induced severe systemic muscle
dysfunction further negatively impacting the performance status, quality of life, and survival. Although much is
known about the contribution of tumor cells, osteoclasts, osteoblasts, stroma cells, and immune cells to the
bone destructive process in OCIB, the role of osteocytes (Ots), the most numerous cell type in the skeleton
and major regulators of bone remodeling, is unknown. Studies leading to this application showed that, although
Ots reside deep in mineralized matrix, they are major contributors to the effects of OCIB. MM cells and Ots
physically interact in vivo, and these interactions activate bidirectional Notch signaling driving MM cell
proliferation and Ot apoptosis, and enhance the osteoclastogenic potential of Ots. MM-Ot interactions increase
RANKL, TNFα, cyclinD1 and Notch1-4 receptor expression in MM cells, and upregulate RANKL and the
inhibitor of bone formation, sclerostin, in Ots. Our studies also suggest that MIP-1 and HMGB1, known
stimulators of RANKL, may also be involved because MM-derived MIP-1 acts directly to increase acid-
induced HMGB1 by Ots. Further, RANKL, MIP-1 and HMGB1-driven bone resorption could also induce
muscle dysfunction in MM. This proposal will test the hypothesis that MM-Ot interactions are major
contributors to OCIB through increasing tumor growth and bone resorption, decreasing bone
formation, and inducing muscle dysfunction. This hypothesis will be advanced by pursuing specific aims
that combine in vitro, ex vivo and in vivo approaches, using osteocytic cell lines, authentic osteocytes, human
and murine MM cells lines, primary MM cells derived from patients, bones from genetically modified mice, and
a mouse model of MM. Aim 1 will determine the impact of bidirectional MM/Ot Notch signaling on OCIB using
genetic and pharmacological tools that interfere with Notch activation. Aim 2 will determine the contribution of
MM- and Ot-derived RANKL to OCIB and the role of HMGB1 and MIP-1 in RANKL regulation. And Aim 3 will
determine the role of sclerostin induced by MM/Ot interactions in tumor burden, bone disease, and muscle
dysfunction induced by OCIB.

## Key facts

- **NIH application ID:** 10249368
- **Project number:** 5R01CA209882-06
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Teresita M. Bellido
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $409,850
- **Award type:** 5
- **Project period:** 2017-03-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249368

## Citation

> US National Institutes of Health, RePORTER application 10249368, Contribution of Osteocytes to the Musculoskeletal Effects of Multiple Myeloma (5R01CA209882-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10249368. Licensed CC0.

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