Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis

Devi Rani Sagar (Corresponding Author), Sadaf Ashraf, Luting Xu, James J. Burston, Matthew R. Menhinick, Caroline L. Poulter, Andrew J. Bennett, David A. Walsh, Victoria Chapman

Research output: Contribution to journalArticle

43 Citations (Scopus)
5 Downloads (Pure)

Abstract

BACKGROUND: Increased subchondral bone turnover may contribute to pain in osteoarthritis (OA).

OBJECTIVES: To investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain.

METHODS: Male Sprague Dawley rats (140-260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1-15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group.

RESULTS: Pre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage.

CONCLUSIONS: Our data suggest that early targeting of osteoclasts may reduce pain associated with OA.

Original languageEnglish
Pages (from-to)1558-1565
Number of pages8
JournalAnnals of the Rheumatic Diseases
Volume73
Issue number8
Early online date30 May 2013
DOIs
Publication statusPublished - Aug 2014

Fingerprint

Osteoprotegerin
Arthralgia
Pathology
Osteoarthritis
Iodoacetates
zoledronic acid
Rats
Pain
Osteoclasts
Joints
Diphosphonates
Therapeutics
Osteophyte
Intra-Articular Injections
Bone Remodeling
Hyperalgesia
Weight-Bearing
Microglia
Proteoglycans
Hematoxylin

Cite this

Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis. / Sagar, Devi Rani (Corresponding Author); Ashraf, Sadaf; Xu, Luting; Burston, James J.; Menhinick, Matthew R.; Poulter, Caroline L.; Bennett, Andrew J.; Walsh, David A.; Chapman, Victoria.

In: Annals of the Rheumatic Diseases, Vol. 73, No. 8, 08.2014, p. 1558-1565.

Research output: Contribution to journalArticle

Sagar, DR, Ashraf, S, Xu, L, Burston, JJ, Menhinick, MR, Poulter, CL, Bennett, AJ, Walsh, DA & Chapman, V 2014, 'Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis', Annals of the Rheumatic Diseases, vol. 73, no. 8, pp. 1558-1565. https://doi.org/10.1136/annrheumdis-2013-203260
Sagar, Devi Rani ; Ashraf, Sadaf ; Xu, Luting ; Burston, James J. ; Menhinick, Matthew R. ; Poulter, Caroline L. ; Bennett, Andrew J. ; Walsh, David A. ; Chapman, Victoria. / Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis. In: Annals of the Rheumatic Diseases. 2014 ; Vol. 73, No. 8. pp. 1558-1565.
@article{10f1c1624bef4e07bff36bc1ec66d94e,
title = "Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis",
abstract = "BACKGROUND: Increased subchondral bone turnover may contribute to pain in osteoarthritis (OA).OBJECTIVES: To investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain.METHODS: Male Sprague Dawley rats (140-260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1-15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group.RESULTS: Pre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage.CONCLUSIONS: Our data suggest that early targeting of osteoclasts may reduce pain associated with OA.",
author = "Sagar, {Devi Rani} and Sadaf Ashraf and Luting Xu and Burston, {James J.} and Menhinick, {Matthew R.} and Poulter, {Caroline L.} and Bennett, {Andrew J.} and Walsh, {David A.} and Victoria Chapman",
note = "Acknowledgements: OPG-Fc was a kind gift from Amgen Ltd. Funding: This work was supported by Arthritis Research UK, grant number 18769",
year = "2014",
month = "8",
doi = "10.1136/annrheumdis-2013-203260",
language = "English",
volume = "73",
pages = "1558--1565",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
publisher = "BMJ Publishing Group",
number = "8",

}

TY - JOUR

T1 - Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis

AU - Sagar, Devi Rani

AU - Ashraf, Sadaf

AU - Xu, Luting

AU - Burston, James J.

AU - Menhinick, Matthew R.

AU - Poulter, Caroline L.

AU - Bennett, Andrew J.

AU - Walsh, David A.

AU - Chapman, Victoria

N1 - Acknowledgements: OPG-Fc was a kind gift from Amgen Ltd. Funding: This work was supported by Arthritis Research UK, grant number 18769

PY - 2014/8

Y1 - 2014/8

N2 - BACKGROUND: Increased subchondral bone turnover may contribute to pain in osteoarthritis (OA).OBJECTIVES: To investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain.METHODS: Male Sprague Dawley rats (140-260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1-15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group.RESULTS: Pre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage.CONCLUSIONS: Our data suggest that early targeting of osteoclasts may reduce pain associated with OA.

AB - BACKGROUND: Increased subchondral bone turnover may contribute to pain in osteoarthritis (OA).OBJECTIVES: To investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain.METHODS: Male Sprague Dawley rats (140-260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1-15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group.RESULTS: Pre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage.CONCLUSIONS: Our data suggest that early targeting of osteoclasts may reduce pain associated with OA.

U2 - 10.1136/annrheumdis-2013-203260

DO - 10.1136/annrheumdis-2013-203260

M3 - Article

VL - 73

SP - 1558

EP - 1565

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

IS - 8

ER -