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Proteolytic regulation of a galectin-3/Lrp1 axis controls osteoclast-mediated bone resorption

Lingxin Zhu1,2,3, Yi Tang2,3, Xiao-Yan Li2,3

  • 1The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University , Wuhan, China.

The Journal of Cell Biology
|March 7, 2023
PubMed

Insights

Matrix metalloproteinases (MMPs) regulate osteoclast function by degrading galectin-3. This process, involving the galectin-3 receptor Lrp1, is crucial for bone resorption and cellular signaling in both mice and humans.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Skeletal Biology

Background:

  • Osteoclasts are critical for bone resorption, utilizing matrix metalloproteinases (MMPs) to degrade type I collagen.
  • The precise substrates and regulatory mechanisms of MMPs in osteoclast function remain incompletely understood.

Purpose of the Study:

  • To identify novel MMP substrates essential for osteoclast activity.
  • To elucidate the molecular mechanisms by which MMPs regulate osteoclast-mediated bone resorption.

Main Methods:

  • Utilized Mmp9/Mmp14 double-knockout (DKO) osteoclasts and MMP-inhibited human osteoclasts.
  • Employed mass spectrometry to identify protein interactions and receptors.
  • Assessed RhoA activation, sealing zone formation, and bone resorption assays.

Main Results:

  • DKO and MMP-inhibited osteoclasts exhibited altered transcriptional programs, impaired RhoA activation, sealing zone formation, and bone resorption.
  • Mmp9 and Mmp14 were found to cooperatively proteolyze cell surface galectin-3.
  • Low-density lipoprotein-related protein-1 (Lrp1) was identified as the galectin-3 receptor, and its targeting rescued osteoclast function in DKO cells.

Conclusions:

  • A novel galectin-3/Lrp1 axis regulates osteoclast function through proteolytic control.
  • This pathway influences both transcriptional programs and intracellular signaling cascades vital for osteoclast activity in mice and humans.

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