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Mechanical strain-mediated reduction in RANKL expression is associated with RUNX2 and BRD2.

Gabriel L Galea1, Christopher R Paradise2, Lee B Meakin3

  • 1Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA; Developmental Biology and Cancer, UCL GOS Institute of Child Health, London, UK; Comparative Bioveterinary Sciences, Royal Veterinary College, London, UK.

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PubMed
Summary
This summary is machine-generated.

Mechanical strain regulates bone remodeling by influencing sclerostin and RANKL. The transcription factor RUNX2 and epigenetic reader BRD2 play key roles in this process, particularly in strain-induced RANKL reduction.

Keywords:
BRD2EpigeneticsMechanical strainRUNX2Receptor activator of nuclear factor-κB ligandSclerostin

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Area of Science:

  • Bone biology
  • Mechanobiology
  • Epigenetics

Background:

  • Mechanical loading influences bone remodeling by modulating osteoblast and osteoclast activity.
  • Osteocytes secrete sclerostin (SOST) to inhibit osteoblasts and express RANKL to recruit osteoclasts.
  • The transcription factor RUNX2 is a key regulator of osteoblast differentiation and targets both SOST and RANKL.

Purpose of the Study:

  • To investigate the role of RUNX2 and epigenetic factors in mediating the effects of mechanical strain on SOST and RANKL expression in osteoblasts.
  • To elucidate the mechanism by which mechanical loading regulates bone remodeling processes.

Main Methods:

  • Human osteoblastic Saos-2 cells were subjected to mechanical strain using a four-point bending device.
  • RUNX2 knockdown was performed using siRNA.
  • Gene expression of SOST, RANKL, and epigenetic modifiers was quantified using RT-qPCR.
  • Chromatin immunoprecipitation (ChIP) was used to assess RUNX2 and BRD2 occupancy at the RANKL promoter.
  • Co-immunoprecipitation was performed to investigate protein-protein interactions between RUNX2 and BRD2.

Main Results:

  • Mechanical strain down-regulated SOST and RANKL expression in Saos-2 cells without altering RUNX2 levels.
  • RUNX2 knockdown increased basal SOST expression but did not affect strain-induced SOST down-regulation.
  • RUNX2 knockdown prevented the strain-induced down-regulation of RANKL.
  • RUNX2 was found to bind to the RANKL promoter, and its occupancy decreased upon strain.
  • Both strain and RUNX2 knockdown reduced the expression of the epigenetic reader BRD2.
  • BRD2 was found to interact with RUNX2 and bind to the RANKL promoter, with its occupancy decreasing upon strain.

Conclusions:

  • RUNX2 contributes to bone remodeling by suppressing basal SOST expression.
  • RUNX2 facilitates the strain-induced down-regulation of RANKL through a mechanosensitive epigenetic mechanism involving BRD2.
  • This RUNX2-BRD2 interaction at the RANKL promoter represents a novel pathway in mechanical load-induced bone remodeling.