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

Abstract

BackgroundIncreased subchondral bone turnover may contribute to pain in osteoarthritis (OA).ObjectivesTo investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain.MethodsMale 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.ResultsPre-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.ConclusionsOur data suggest that early targeting of osteoclasts may reduce pain associated with OA.

Targeting the D Series Resolvin Receptor System for the Treatment of Osteoarthritis Pain

“…Synovial inflammation was graded on a scale of 0 (lining layer, 1–2 cells thick) to 3 (lining layer >9 cells thick and/or severe increase in cellularity), as previously described 29. Sections from the posterior half of the knee joints were dewaxed and recalcified with calcium chloride and magnesium chloride before tartrate‐resistant acid phosphatase (TRAP) staining was conducted using a commercially available kit (F386A; Sigma‐Aldrich).…”

Effects of Dietary Saturated Fatty Acids on the Onset and Progression of Osteoarthritis in Rat Knee Joints

“…Allodynia from central sensitization could play an important role in the reduction of this pain threshold. The common drivers of nociceptors associated with OA are the subchondral bone, muscle, ligaments, and synovium [283,284]. The diverse inflammation expression in response to the different SFA diets could hold key to this finding, as we observed HLA diet group rats to exhibit decreased pro-inflammatory cytokines.…”

“…The pathology of the subchondral bone region has been in the spotlight for many years for its role in cartilage damage in OA [332]. Apart from cartilage degradation, bone loss is known to be one of the main components of pain progression in OA, which is followed up by sclerosis of the subchondral bone plate [283,333]. As a result of the increased subchondral bone alterations and cartilage damage, increased activation of astrocytes and microglia were also observed as previously shown [334].…”

“…Pain, as we may know results from both increased nociceptive inputs from the joints and also central sensitization of the SC and the brain [283]. Allodynia from central sensitization could play an important role in the reduction of this pain threshold.…”

Subchondral bone and osteoarthritis

“…Zoledronic acid [58] or other bisphosphonates [59], cathepsin K inhibitors [60], osteoprotegerin [61], or strontium ranelate [62] have recently been shown to decrease joint structural degradation and/or pain. However, the translation to human clinical studies was often quite disappointing.…”