AI Article Synopsis

  • Obesity leads to changes in the microRNA profile of extracellular vesicles released by bone marrow macrophages, which impact the differentiation of skeletal stem/progenitor cells (SSPCs) into either bone-building osteoblasts or fat-storing adipocytes, resulting in bone deterioration.
  • Macrophage-derived extracellular vesicles from obese mice cause significant bone loss when introduced to lean mice, while those from lean mice can improve bone health in obese mice.
  • Specific microRNAs, such as miR-140 and miR-378a, play opposing roles in regulating SSPC differentiation; targeting these microRNAs through an innovative delivery method restores bone health in obese mice, highlighting the role of bone marrow macrophages in obesity-related bone issues

Article Abstract

Obesity-induced chronic inflammation exacerbates multiple types of tissue/organ deterioration and stem cell dysfunction; however, the effects on skeletal tissue and the underlying mechanisms are still unclear. Here, we show that obesity triggers changes in the microRNA profile of macrophage-secreted extracellular vesicles, leading to a switch in skeletal stem/progenitor cell (SSPC) differentiation between osteoblasts and adipocytes and bone deterioration. Bone marrow macrophage (BMM)-secreted extracellular vesicles (BMM-EVs) from obese mice induced bone deterioration (decreased bone volume, bone microstructural deterioration, and increased adipocyte numbers) when administered to lean mice. Conversely, BMM-EVs from lean mice rejuvenated bone deterioration in obese recipients. We further screened the differentially expressed microRNAs in obese BMM-EVs and found that among the candidates, miR-140 (with the function of promoting adipogenesis) and miR-378a (with the function of enhancing osteogenesis) coordinately determine SSPC fate of osteogenic and adipogenic differentiation by targeting the Pparα-Abca1 axis. BMM miR-140 conditional knockout mice showed resistance to obesity-induced bone deterioration, while miR-140 overexpression in SSPCs led to low bone mass and marrow adiposity in lean mice. BMM miR-378a conditional depletion in mice led to obesity-like bone deterioration. More importantly, we used an SSPC-specific targeting aptamer to precisely deliver miR-378a-3p-overloaded BMM-EVs to SSPCs via an aptamer-engineered extracellular vesicle delivery system, and this approach rescued bone deterioration in obese mice. Thus, our study reveals the critical role of BMMs in mediating obesity-induced bone deterioration by transporting selective extracellular-vesicle microRNAs into SSPCs and controlling SSPC fate.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11282946PMC
http://dx.doi.org/10.1016/j.bioactmat.2024.06.035DOI Listing

Publication Analysis

Top Keywords

bone deterioration
32
extracellular vesicles
12
bone
12
lean mice
12
deterioration
10
skeletal stem/progenitor
8
stem/progenitor cell
8
obese mice
8
deterioration obese
8
sspc fate
8

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!