Engineered myeloid precursors differentiate into osteoclasts and resorb heterotopic ossification in mice

Cameron Rementer; Apichai Yavirach; Worakanya Buranaphatthana; Philip A Walczak; Mei Speer; Kat Pierce; Subramanian Dharmarajan; Elizabeth Leber; Bruce Sangiorzan; Steven Bain; Marta Scatena; Alexander Blümke; Cecilia M Giachelli

doi:10.3389/fbioe.2024.1491962

Engineered myeloid precursors differentiate into osteoclasts and resorb heterotopic ossification in mice

Front Bioeng Biotechnol. 2024 Nov 22:12:1491962. doi: 10.3389/fbioe.2024.1491962. eCollection 2024.

Authors

Cameron Rementer^#¹, Apichai Yavirach^#^{2

3}, Worakanya Buranaphatthana^#^{2

4}, Philip A Walczak^#^{1

2}, Mei Speer¹, Kat Pierce¹, Subramanian Dharmarajan¹, Elizabeth Leber¹, Bruce Sangiorzan⁵, Steven Bain⁵, Marta Scatena¹, Alexander Blümke^#^{1

6}, Cecilia M Giachelli^#¹

Affiliations

¹ Department of Bioengineering, School of Medicine, University of Washington, Seattle, WA, United States.
² Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States.
³ Department of Prosthodontics, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
⁴ Department of Oral Biology and Oral Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
⁵ Department of Orthopedics and Sports Medicine, University of Washington, Seattle, WA, United States.
⁶ Department of Orthopedics and Trauma Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

^# Contributed equally.

Abstract

Introduction: Heterotopic ossification (HO) occurs following orthopedic trauma, spinal cord injuries, brain trauma and limb amputations. Once symptomatic, HO causes pain, limited mobility and decreased quality of life. Current treatments are limited and have significant complications with high recurrence rates, underscoring the need for improved therapeutic interventions. Osteoclasts (OCs) are physiological bone resorptive cells that secrete enzymes and protons to degrade bone.

Methods: In this study, we describe the use of genetically engineered OCs as a novel cell therapy approach to treat HO. Inducible, engineered myeloid precursors (iRANK cells) treated with a chemical inducer of dimerization (CID) differentiated into TRAP⁺ multinucleated OCs and resorbed mineralized tissues in vitro.

Results: In vivo, BMP-2-induced murine HO lesions were significantly regressed following treatment using iRANK cells with concomitant systemic administration of CID. Moreover, many OCs were TRAP⁺, MMP9⁺, and GFP⁺, indicating that they differentiated from delivered iRANK cells.

Discussion: In summary, these data con rm the ability of engineered myeloid precursors to differentiate into OCs and resorb HO in vivo paving the way for OC delivery as a promising approach for HO treatment.

Keywords: RANK; bone; chemical inducer of dimerization; engineered osteoclasts; heterotopic ossification; osteoclasts; resorption.

Abstract

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