4.7 Article

Direct Reprogramming of Mouse Subchondral Bone Osteoblasts into Chondrocyte-like Cells

Journal

BIOMEDICINES
Volume 10, Issue 10, Pages -

Publisher

MDPI
DOI: 10.3390/biomedicines10102582

Keywords

cellular reprogramming; transcription factor; osteoblast; chondrocyte; c-Myc; Plagl1; Sox5; Sox9

Funding

  1. National Natural Science Foundation of China [81871784, 82171822]
  2. Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study Project [BZ0150]

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In this study, osteoblasts from subchondral bone were successfully reprogrammed into chondrocytes, and different combinations of transcription factors were found to guide the reprogramming towards different subpopulations of chondrocytes. These findings have important implications for developing new strategies to treat full-thickness cartilage defects.
Treatment of full-thickness articular cartilage defects with exposure of subchondral bone often seen in osteoarthritic conditions has long been a great challenge, especially with a focus on the feasibility of in situ cartilage regeneration through minimally invasive procedures. Osteoblasts that situate in the subchondral bone plate may be considered a potentially vital endogenous source of cells for cartilage resurfacing through direct reprogramming into chondrocytes. Microarray-based gene expression profiles were generated to compare tissue-specific transcripts between subchondral bone and cartilage of mice and to assess age-dependent differences of chondrocytes as well. On osteoblast cell lines established from mouse proximal tibial subchondral bone, sequential screening by co-transduction of transcription factor (TF) genes that distinguish chondrocytes from osteoblasts reveals a shortlist of potential reprogramming factors exhibiting combined effects in inducing chondrogenesis of subchondral bone osteoblasts. A further combinatorial approach unexpectedly identified two 3-TF combinations containing Sox9 and Sox5 that exhibit differences in reprogramming propensity with the third TF c-Myc or Plagl1, which appeared to direct the converted chondrocytes toward either a superficial or a deeper zone phenotype. Thus, our approach demonstrates the possibility of converting osteoblasts into two major chondrocyte subpopulations with two combinations of three genes (Sox9, Sox5, and c-Myc or Plagl1). The findings may have important implications for developing novel in situ regeneration strategies for the reconstruction of full-thickness cartilage defects.

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