Dataset Information

Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology.

ABSTRACT:

Objective

Proteinase-activated receptor 2 (PAR2) deficiency protects against cartilage degradation in experimental osteoarthritis (OA). The wider impact of this pathway upon OA-associated pathologies such as osteophyte formation and pain is unknown. Herein, we investigated early temporal bone and cartilage changes in experimental OA in order to further elucidate the role of PAR2 in OA pathogenesis.

Methods

OA was induced in wild-type (WT) and PAR2-deficient (PAR2^-/-) mice by destabilisation of the medial meniscus (DMM). Inflammation, cartilage degradation and bone changes were monitored using histology and microCT. In gene rescue experiments, PAR2^-/- mice were intra-articularly injected with human PAR2 (hPAR2)-expressing adenovirus. Dynamic weight bearing was used as a surrogate of OA-related pain.

Results

Osteophytes formed within 7?days post-DMM in WT mice but osteosclerosis was only evident from 14?days post induction. Importantly, PAR2 was expressed in the proliferative/hypertrophic chondrocytes present within osteophytes. In PAR2^-/- mice, osteophytes developed significantly less frequently but, when present, were smaller and of greater density; no osteosclerosis was observed in these mice up to day 28. The pattern of weight bearing was altered in PAR2^-/- mice, suggesting reduced pain perception. The expression of hPAR2 in PAR2^-/- mice recapitulated osteophyte formation and cartilage damage similar to that observed in WT mice. However, osteosclerosis was absent, consistent with lack of hPAR2 expression in subchondral bone.

Conclusions

This study clearly demonstrates PAR2 plays a critical role, via chondrocytes, in osteophyte development and subchondral bone changes, which occur prior to PAR2-mediated cartilage damage. The latter likely occurs independently of OA-related bone changes.

SUBMITTER: Huesa C

PROVIDER: S-EPMC5099200 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Publications

Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology.

Huesa Carmen C Ortiz Ana C AC Dunning Lynette L McGavin Laura L Bennett Louise L McIntosh Kathryn K Crilly Anne A Kurowska-Stolarska Mariola M Plevin Robin R van 't Hof Rob J RJ Rowan Andrew D AD McInnes Iain B IB Goodyear Carl S CS Lockhart John C JC Ferrell William R WR

Annals of the rheumatic diseases 20151223 11

<h4>Objective</h4>Proteinase-activated receptor 2 (PAR2) deficiency protects against cartilage degradation in experimental osteoarthritis (OA). The wider impact of this pathway upon OA-associated pathologies such as osteophyte formation and pain is unknown. Herein, we investigated early temporal bone and cartilage changes in experimental OA in order to further elucidate the role of PAR2 in OA pathogenesis.<h4>Methods</h4>OA was induced in wild-type (WT) and PAR2-deficient (PAR2<sup>-/-</sup>) mi ...[more]

PMID: 26698846

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Project description:AimsTo investigate the impact of subchondral bone cysts (SBCs) in stress-induced osseous and articular variations in cystic and non-cystic knee models using finite element analysis.Materials and methods3D knee joint models were reconstructed from computed tomography (CT) and magnetic resonance imaging (MRI). Duplicate 3D models were also created with a 3D sphere mimicking SBCs in medial tibia. Models were divided into three groups. In group A, a non-cystic knee model was used, whereas in groups B and C, SBCs of 4 and 12 mm size were simulated, respectively. Cyst groups were further divided into three sub-groups. Each of sub-group 1 was composed of a solitary SBC in the anterior half of tibia adjacent to joint line. In sub-group 2, a solitary cyst was modeled at a lower-joint location, and in sub-group 3, two SBCs were used. All models were vertically loaded with weights representing double- and single-leg stances.ResultsDuring single-leg stance, increase in subchondral bone stress in sub-groups B-1 and B-3 were significant (p = 0.044, p = 0.026). However, in sub-group B-2, a slight increase was observed than non-cystic knee model (9.93 ± 1.94 vs. 9.35 ± 1.85; p = 0.254). All the sub-groups in group C showed significantly increased articular stress (p < 0.001). Conversely, a prominent increase in peri-cystic cancellous bone stress was produced by SBCs in groups B and C (p < 0.001). Mean cartilage shear stress in sub-groups B-1 and B-2 (0.66 ± 0.56, 0.58 ± 0.54) was non-significant (p = 0.374, p = 0.590) as compared to non-cystic model (0.47 ± 0.67). But paired cysts of the same size (B-3) produced a mean stress of 0.98 ± 0.49 in affected cartilage (p = 0.011). Models containing 12 mm SBCs experienced a significant increase in cartilage stress (p = 0.001, p = 0.006, p < 0.001) in sub-groups C-1, C-2, and C-3 (1.25 ± 0.69, 1.01 ± 0.54, and 1.26 ± 0.59), respectively.ConclusionThe presence of large-sized SBCs produced an increased focal stress effect in articular cartilage. Multiple cysts further deteriorate the condition by increased osseous stress effect and high tendency of peripheral cyst expansion in simulated cystic knee models than non-cystic knee models.

Dataset Information

Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology.

Objective

Methods

Results

Conclusions

Publications

Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology.

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