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

Abstract

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.Osteoarthritis (OA) is the most common form of arthritis and a leading cause of long-term disability. With increasing life expectancy, OA is a major socioeconomic and clinical concern, as no curative treatment yet exists. While considerable advancement has been made toward a better understanding of the pathophysiology of the disease process, there is still much to be accomplished before a disease-modifying OA drug is developed that can effectively reduce or stop the disease progression. It is therefore of the utmost importance to identify new candidates that can contribute to the development of therapeutic agents to prevent or arrest the disease process.Although the hallmark of OA is the progressive degeneration of articular cartilage, the subchondral bone is also suggested to be an active component of the OA process in humans (1-4). The rationale is that because the subchondral bone plate is in direct contact with the cartilage, it influences not only mechanical effects, but also cartilage degradation by providing catabolic factors to this overlying tissue, thus promoting Dr.

The chemokine receptor CCR5 plays a role in post-traumatic cartilage loss in mice, but does not affect synovium and bone

“…In spite of studies that report use of sham and operated knees in different mice 32,45 , there are also reports using sham and surgery-operated knees within the same animal 29,46 . Interestingly, in unpublished observations, we noted that the measurements of bone parameters of sham-operated knees differed depending on whether the contralateral knee was itself a sham or DMM-operated knee.…”

Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis

“…OA was surgically induced in 10-week-old control and mTOR KO male mice by DMM or sham surgery (control) in the right knee, as previously described 18 19. Histological and biochemical analysis were performed at 5 and 10 weeks post-OA surgery.…”

The Therapeutic Effect of rhMK on Osteoarthritis in Mice, Induced by Destabilization of the Medial Meniscus

“…[48][49][50][51][52][53][54] In the DMM OA model on C57BL/6 mice, the DMM induced mechanical allodynia and activity obstacle coincidently with cartilage injury was found after 15 weeks of DMM surgery. Similar results also demonstrated by other groups, 26,39,55) but in their research, the slight pathological change on cartilage was found 9 weeks after the DMM surgery, different from 15 weeks in our DMM model.…”