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Bone Mass Is Compromised by the Chemotherapeutic Trabectedin in Association With Effects on Osteoblasts and
Benjamin P Sinder1, Laura Zweifler1, Amy J Koh1
1Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
Abstract:
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-week-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-week) treatment of 16-week-old 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 bone volume fraction (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. © 2017 American Society for Bone and Mineral Research.
Insights
Trabectedin reduces bone mass by harming macrophages and impairing efferocytosis, the clearance of dead cells. This chemotherapy also directly affects bone-forming cells, impacting bone health.
Area of Science:
- Bone Biology and Macrophage Biology
- Cellular Homeostasis and Phagocytosis
Background:
- Macrophages play a role in bone formation, but their phagocytic function in bone homeostasis is unclear.
- Osteoblast apoptosis is a natural process, and efferocytosis of these cells is crucial for tissue homeostasis.
Purpose of the Study:
- To investigate the effects of macrophage depletion and impaired phagocytosis on bone using trabectedin.
- To determine if trabectedin affects macrophage efferocytosis of apoptotic osteoblasts and subsequent osteoinductive signaling.
Main Methods:
- Male C57BL/6J mice were treated with trabectedin to deplete macrophages and assess its effects on bone parameters.
- In vitro studies evaluated trabectedin's impact on macrophage efferocytosis of apoptotic osteoblasts and TGF-β production.
- Bone mineral density, trabecular bone volume, osteoclast surface, and bone formation markers were measured.
Main Results:
- Trabectedin reduced macrophages, phagocytic gene expression, and efferocytosis capacity in vivo and in vitro.
- Trabectedin treatment led to reduced trabecular bone volume, cortical bone mineral density, and bone formation markers.
- While trabectedin affected osteoblasts directly, intermittent parathyroid hormone (1-34) treatment partially rescued bone loss in treated mice.
Conclusions:
- Trabectedin significantly reduces bone mass by compromising macrophages, efferocytosis, and directly impacting osteoblasts.
- The findings highlight the clinical relevance of trabectedin's skeletal side effects in cancer patients.
- Targeting macrophage efferocytosis may offer therapeutic strategies for bone loss associated with trabectedin treatment.
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