In vivo bone-specific EphB4 overexpression in mice protects both subchondral bone and cartilage during osteoarthritis

Arthritis Rheum. 2012 Nov;64(11):3614-25. doi: 10.1002/art.34638.


Objective: In vitro activation of the receptor EphB4 positively affects human osteoarthritis (OA) articular cell metabolism. However, the specific in vivo role of this ephrin receptor in OA remains unknown. We investigated in mice the in vivo effect of bone-specific EphB4 overexpression on OA pathophysiology.

Methods: Morphometric, morphologic, and radiologic evaluations were performed on postnatal day 5 (P5) mice and on 10-week-old mice. Knee OA was induced surgically by destabilization of the medial meniscus (DMM) in 10-week-old male EphB4 homozygous transgenic (EphB4-Tg) and wild-type (WT) mice. Medial compartment evaluations of cartilage were performed using histology and immunohistochemistry, and evaluations of subchondral bone using histomorphometry, osteoclast staining, and micro-computed tomography.

Results: There was no obvious phenotype difference in skeletal development between EphB4-Tg mice and WT mice at P5 or at 10 weeks. At 8 and 12 weeks post-DMM, the EphB4-Tg mice demonstrated significantly less cartilage alteration in the medial tibial plateau and the femoral condyle than did the WT mice. This was associated with a significant reduction of aggrecan and type II collagen degradation products, type X collagen, and collagen fibril disorganization in the operated EphB4-Tg mice. The medial tibial subchondral bone demonstrated a significant reduction in sclerosis, bone volume, trabecular thickness, and number of tartrate-resistant acid phosphatase-positive osteoclasts at both times assessed post-DMM in the EphB4-Tg mice than in the WT mice.

Conclusion: This is the first in vivo evidence that bone-specific EphB4 overexpression exerts a protective effect on OA joint structural changes. The findings of this study stress the in vivo importance of subchondral bone biology in cartilage integrity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cartilage, Articular / immunology
  • Cartilage, Articular / metabolism
  • Cartilage, Articular / pathology*
  • Disease Models, Animal
  • Edema / immunology
  • Edema / pathology
  • Female
  • Femur / immunology
  • Femur / metabolism
  • Femur / pathology*
  • Gene Expression / immunology
  • Genotype
  • Knee Joint / immunology
  • Knee Joint / pathology
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Osteoarthritis, Knee* / genetics
  • Osteoarthritis, Knee* / immunology
  • Osteoarthritis, Knee* / pathology
  • Phenotype
  • Receptor, EphB4 / genetics*
  • Receptor, EphB4 / immunology
  • Tibia / immunology
  • Tibia / metabolism
  • Tibia / pathology*


  • Biomarkers
  • Ephb4 protein, mouse
  • Receptor, EphB4