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

Carmen Huesa, Ana C Ortiz, Lynette Dunning, Laura McGavin, Louise Bennett, Kathryn McIntosh, Anne Crilly, Mariola Kurowska-Stolarska, Robin Plevin, Rob J van ,t Hof, Andrew D Rowan, Iain B McInnes, Carl S Goodyear, John C Lockhart, William R Ferrell

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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. 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. 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. 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.
LanguageEnglish
Number of pages11
JournalAnnals of the Rheumatic Diseases
Early online date23 Dec 2015
DOIs
Publication statusE-pub ahead of print - 23 Dec 2015

Fingerprint

PAR-2 Receptor
Cartilage
Pathology
Osteoarthritis
Bone
Osteophyte
Bone and Bones
Pain
Osteosclerosis
Bearings (structural)
Tibial Meniscus
Weight-Bearing
Chondrocytes
Degradation
X-Ray Microtomography
Pain Perception
Histology
Temporal Bone
Bone Development
Adenoviridae

Keywords

  • cartilage degradation
  • osteoarthritis
  • OA pathogenesis
  • bone changes

Cite this

Huesa, Carmen ; Ortiz, Ana C ; Dunning, Lynette ; McGavin, Laura ; Bennett, Louise ; McIntosh, Kathryn ; Crilly, Anne ; Kurowska-Stolarska, Mariola ; Plevin, Robin ; van ,t Hof, Rob J ; Rowan, Andrew D ; McInnes, Iain B ; Goodyear, Carl S ; Lockhart, John C ; Ferrell, William R. / Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology. In: Annals of the Rheumatic Diseases. 2015.
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abstract = "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. 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. 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. 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.",
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year = "2015",
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Huesa, C, Ortiz, AC, Dunning, L, McGavin, L, Bennett, L, McIntosh, K, Crilly, A, Kurowska-Stolarska, M, Plevin, R, van ,t Hof, RJ, Rowan, AD, McInnes, IB, Goodyear, CS, Lockhart, JC & Ferrell, WR 2015, 'Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology' Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2015-208268

Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology. / Huesa, Carmen; Ortiz, Ana C; Dunning, Lynette; McGavin, Laura; Bennett, Louise; McIntosh, Kathryn; Crilly, Anne; Kurowska-Stolarska, Mariola; Plevin, Robin; van ,t Hof, Rob J; Rowan, Andrew D; McInnes, Iain B; Goodyear, Carl S; Lockhart, John C; Ferrell, William R.

In: Annals of the Rheumatic Diseases, 23.12.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology

AU - Huesa, Carmen

AU - Ortiz, Ana C

AU - Dunning, Lynette

AU - McGavin, Laura

AU - Bennett, Louise

AU - McIntosh, Kathryn

AU - Crilly, Anne

AU - Kurowska-Stolarska, Mariola

AU - Plevin, Robin

AU - van ,t Hof, Rob J

AU - Rowan, Andrew D

AU - McInnes, Iain B

AU - Goodyear, Carl S

AU - Lockhart, John C

AU - Ferrell, William R

PY - 2015/12/23

Y1 - 2015/12/23

N2 - 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. 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. 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. 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.

AB - 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. 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. 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. 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.

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KW - osteoarthritis

KW - OA pathogenesis

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