# Megakaryocytic TGFβ1 orchestrates osteogenesis of LepR+ SSCs to alleviate radiation-induced bone loss

## TL;DR

This study shows that megakaryocytes help repair radiation-damaged bones by supporting stem cells through TGFβ1 and zinc signaling.

## Contribution

The novel finding is that megakaryocytic TGFβ1 promotes osteogenesis of LepR+ SSCs by facilitating zinc influx and reducing endoplasmic reticulum stress.

## Key findings

- Deficiency of megakaryocytes impairs bone formation and reduces LepR+ SSC numbers.
- Megakaryocytic TGFβ1 promotes osteogenic differentiation of LepR+ SSCs after irradiation.
- Zinc influx via Slc39a14 activation reduces ER stress and promotes osteogenesis.

## Abstract

It has been reported that a close relationship exists between the hematopoietic and skeletal systems, and megakaryocytes (MKs) may play a role in maintaining bone homeostasis. However, the precise role and underlying mechanisms of MKs in osteogenesis, particularly under stress conditions, remain largely unknown. Here we demonstrate that deficiency of MKs significantly impairs bone formation, accompanied by a reduction in the number of leptin receptor positive skeletal stem cells (LepR+ SSCs) in MKs conditionally deleted mice. Further investigations reveal that megakaryocytic TGFβ1 promotes the osteogenic differentiation of LepR+ SSCs following irradiation. Notably, thrombopoietin treatment effectively maintains the number of LepR+ SSCs and stimulates bone formation. Moreover, MKs-derived TGFβ1 facilitates zinc ions influx into LepR+ SSCs by activating Slc39a14, thereby alleviating endoplasmic reticulum stress after irradiation. In addition, the increased intracellular zinc levels inhibit PTP1B expression and activate Stat3 signaling, promoting osteogenic lineage commitment. In conclusion, our findings demonstrate that the megakaryocytic TGFβ1 orchestrates the osteogenesis of LepR+ SSCs following irradiation, offering a potential therapeutic strategy for radiation-induced bone loss.

This study explores how certain cells in our bones, called skeletal stem cells (SSCs), help maintain bone health and repair damage. The researchers found that a small group of cells, known as leptin receptor-positive (LepR+) SSCs, are crucial for bone repair. The study focused on how megakaryocytes (MKs), a type of bone marrow cell, support these SSCs. The researchers used mice to study the effects of radiation on bones and how MKs help LepR+ SSCs recover. They discovered that MKs release a protein called TGFβ1, which helps LepR+ SSCs absorb zinc ions. This process reduces stress in the cells and encourages them to become osteoblasts. The study also showed that increasing MKs in the bone marrow can improve bone strength after radiation. In conclusion, MKs play a vital role in bone repair by supporting LepR+ SSCs. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.