Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis.
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.
['Sagar|Devi Rani|DR|', 'Ashraf|Sadaf|S|', 'Xu|Luting|L|', 'Burston|James J|JJ|', 'Menhinick|Matthew R|MR|', 'Poulter|Caroline L|CL|', 'Bennett|Andrew J|AJ|', 'Walsh|David A|DA|', 'Chapman|Victoria|V|']
D000818:Animals D018771:Arthralgia D001522:Behavior, Animal D050071:Bone Density Conservation Agents D016723:Bone Remodeling D004164:Diphosphonates D004195:Disease Models, Animal D015195:Drug Design D004791:Enzyme Inhibitors D007093:Imidazoles D019807:Iodoacetic Acid D007596:Joints D008297:Male D009619:Nociceptors D010003:Osteoarthritis D010010:Osteoclasts D054850:Osteophyte D053244:Osteoprotegerin D051381:Rats D017207:Rats, Sprague-Dawley D013116:Spinal Cord D000077211:Zoledronic Acid
Osteoarthritis Knee Osteoarthritis Synovitis