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Updated: Jun 15, 2025

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Time- and cell-specific activation of BMP signaling restrains chondrocyte hypertrophy

Stephen J Gadomski1,2,3, Byron W H Mui1,3,4,5, Raphael Gorodetsky6

  • 1Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.

Iscience
|August 28, 2024
PubMed

Insights

Human bone marrow stromal cells (hBMSCs) form cartilage on hyaluronic acid-coated fibrin microbeads (HyA-FMBs). This study clarifies the mechanism, showing engineered chondrospheroids create stable, non-hypertrophic cartilage in vivo.

Area of Science:

  • Regenerative Medicine
  • Stem Cell Biology
  • Cartilage Tissue Engineering

Background:

  • Current stem cell therapies for degenerative cartilage disease are hindered by a lack of understanding regarding hyaline cartilage formation and maintenance.
  • Human bone marrow stromal cells/skeletal stem cells (hBMSCs/SSCs) can produce stable hyaline cartilage when cultured on hyaluronic acid-coated fibrin microbeads (HyA-FMBs), but the underlying mechanisms are not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which hBMSCs/SSCs form stable hyaline cartilage on HyA-FMBs.
  • To investigate the role of bone morphogenetic protein (BMP) signaling in chondrogenesis using engineered human-induced pluripotent stem cell (hiPSC)-derived sclerotome cells.

Main Methods:

  • Cultured hBMSC/SSC/HyA-FMB organoids to analyze BMP signaling dynamics during chondrogenic differentiation.
  • Established hiPSC-derived sclerotome cells and treated them with transforming growth factor β (TGF-β) alone or in combination with BMP2 and growth differentiation factor 5 (GDF5).
  • Assessed chondrospheroid formation and gene expression markers (COL2A1, ACAN, PRG4, COL10A1, ALP) in vitro and evaluated cartilage formation after transplantation in immunocompromised rodents.

Main Results:

  • hBMSC/SSC/HyA-FMB organoids showed transiently reduced BMP signaling early in differentiation, followed by restoration in chondrogenic IGFBP5+/MGP+ cells.
  • TGF-β/BMP2/GDF5 treatment of hiPSC-derived sclerotome cells induced SOX9+ chondrospheroids with high expression of key cartilage matrix genes (COL2A1, ACAN, PRG4) and low expression of hypertrophic markers (COL10A1, ALP).
  • Transplantation of chondrospheroid-derived cells/HyA-FMBs resulted in the formation of persistent, non-hypertrophic cartilage in vivo, unlike transplanted hBMSCs/SSCs/HyA-FMBs.

Conclusions:

  • The study clarifies the BMP signaling pathway crucial for hyaline cartilage formation using hBMSCs/SSCs on HyA-FMBs.
  • Engineered chondrospheroids derived from hiPSC sclerotome cells effectively generate stable, non-hypertrophic cartilage in vivo, offering a promising cell source for cartilage repair.

Keywords:
Physiologycell biologymolecular biologystem cells research

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