14 junio 2017

Yondelis . Bone Mass is Compromised by the Chemotherapeutic Trabectedin in Association with Effects on Osteoblasts and Macrophage Efferocytosis.

American Society for Bone and Mineral Research // 2017 Jun 10.

Resultado de imagen de TrabectedinSinder BP, Zweifler L, Koh AJ, Michalski MN, Hofbauer LC, Aguirre JI, Roca H, McCauley LK.

Authors information

*.- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI.

*.- Center for Healthy Aging, Technische Universität Dresden Technical University Medical Center, Dresden, Germany.

*.- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, FL.

*.- Department of Pathology, University of Michigan, Medical School, Ann Arbor, MI.


Macrophages have established roles supporting bone formation. Despite their professional phagocytic nature, the role of macrophage phagocytosis in bone homeostasis is not well understood. Interestingly, apoptosis is a pivotal feature of cellular regulation and the primary fate of osteoblasts is apoptosis.

Efferocytosis (phagocytosis of apoptotic cells) is a key physiologic process for the homeostasis of many tissues, and is associated with expression of osteoinductive factors. To test effects of macrophage depletion and compromised phagocytosis on bone, 16 wk old male C57BL/6J mice were treated with trabectedin - a chemotherapeutic with established anti-macrophage effects.

Trabectedin treatment reduced F4/80+ and CD68+ macrophages in the bone marrow as assessed by flow cytometry, osteal macrophages near the bone surface, and macrophage viability in vitro.

Trabectedin treatment significantly reduced marrow gene expression of key phagocytic factors (Mfge8, Mrc1), and macrophages from treated mice had a reduced ability to phagocytose apoptotic mimicry beads.

Macrophages cultured in vitro and treated with trabectedin displayed reduced efferocytosis of apoptotic osteoblasts. 

Moreover, efferocytosis increased macrophage osteoinductive TGF-β production and this increase was inhibited by trabectedin.

Long-term (6 wk) treatment of 16 wk C57BL/6J mice with trabectedin significantly reduced trabecular BV/TV and cortical BMD. Although trabectedin reduced osteoclast numbers in vitro, osteoclast surface in vivo was not altered.

Trabectedin treatment reduced serum P1NP as well as MS/BS and BFR/BS, and inhibited mineralization and Runx2 gene expression of osteoblast cultures. Finally, intermittent PTH 1-34 (iPTH) treatment was administered in combination with trabectedin, and iPTH increased trabecular BV/TV in trabectedin treated mice.

Collectively, the data support a model whereby trabectedin significantly reduces bone mass due to compromised macrophages and efferocytosis, but also due to direct effects on osteoblasts.

This data has immediate clinical relevance in light of increasing use of trabectedin in oncology .

Resultado de imagen de Trabectedin  Macrophage Efferocytosis.