Effects of pamidronate disodium on the loss of osteoarthritic subchondral bone and the expression of cartilaginous and subchondral osteoprotegerin and RANKL in rabbits

Abstract

BackgroundOsteoarthritis (OA) is a major health problem in the increasingly elderly population. Therefore, it is crucial to prevent and treat OA at an early stage. The present study investigated whether pamidronate disodium (PAM), a bone-loss inhibitor, can significantly prevent or reverse the progression of early anterior cruciate ligament transection (ACLT)-induced OA. Whether therapeutic intervention is associated with regulation of the expression of osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL), metalloproteinase-9 (MMP-9) or Toll-like receptor-4 (TLR-4) in cartilage and/or subchondral bone was also investigated.Methods60 New Zealand rabbits were randomized into four groups: Sham-operated (n = 20); ACLT (n = 20); short-term treatment with PAM (PAM-S, n = 10) and long-term treatment with PAM (PAM-L, n = 10). For cartilage and subchondral bone testing, rabbits from Sham and ACLT groups were harvested at 2, 4, 6, and 14 weeks. Rabbits were given PAM from the 4th week after ACLT operation in PAM-S and PAM-L group, and were harvested at 6 and 14 weeks, respectively. Trabecular characteristics and cartilage changes were detected using Micro-CT, safranin O and rapid green staining, respectively. Immunohistochemical staining for OPG and RANKL were also performed. OPG, RANKL, MMP-9 and TLR-4 expression was evaluated by western blot analysis.ResultsMicro-CT and histology analyses indicated that PAM treatment for 2 or 10 weeks could completely prevent or reverse osteoarthritic subchondral bone loss and cartilage surface erosion. Immunohistochemistry and western blot analysis indicated that expression of OPG and RANKL increased, although RANKL expression increased more significantly than that of OPG. Therefore the ratio of OPG to RANKL was lower in the ACLT group. However, the ratio of OPG to RANKL in the PAM group was significantly higher than that in the ACLT group. Additionally, expression of MMP-9 and TLR-4 were upregulated in the ACLT group and downregulated in the PAM treated groups.ConclusionsPAM can significantly inhibit and even reverse early osteoarthritic subchondral bone loss, thus alleviating the process of cartilaginous degeneration. The mechanisms involved may be associated with the upregulation of OPG expression, and downregulation of RANKL, MMP-9 and TLR-4 expression.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2474-15-370) contains supplementary material, which is available to authorized users.

Sotrastaurin, a PKC inhibitor, attenuates RANKL‐induced bone resorption and attenuates osteochondral pathologies associated with the development of OA

“…For example, Alendronate was found to prevent OA bone pathologies of subchondral bone loss and osteophyte formation as well as articular cartilage degeneration in a chronic OA model in rats 36 . Similar findings were also seen with Pamidronate which completely inhibited subchondral bone loss and prevented the development of OA in a rabbit model of anterior cruciate ligament transection (ACLT)‐induced OA 37 . Pamidronate also protected Runx2 transgenic mice (mice with high bone remodelling) from bone loss associated with partial medial meniscectomy‐induced OA 38 .…”

β2-adrenergic signal transduction plays a detrimental role in subchondral bone loss of temporomandibular joint in osteoarthritis

“…Loss of subchondral bone further triggers degradation of the overlying cartilage through aggravation of the biomechanical environment 7 . Bone resorption inhibitors such as pamidronate disodium 8 , bisphosphonates 9 , strontium ranelate 10 and osteoprotegerin 11 have been shown to reduce pathological features associated with OA in experimental animal models. These results highlight the necessity for better understanding of the biological factors involved in pathological remodeling of subchondral bone in OA.…”

Cell-molecular interactions at the border of articular cartilage and subchondral bone

“…Лише окремі кісткові клітини виявляли імунореактивність, а в нормальному суглобовому хрящі (хибнооперовані тварини) експресію молекул OPG і RANKL встановлено лише в поверхневій зоні. Аналогічні дані щодо експресії цих молекул в нормі лише в поверхневій зоні суглобового хряща наведено іншими дослідниками [30]. На рівні остеохондрального з'єднання щільність імунореактивних клитин була низькою, проте відомо, що розчинні молекули OPG і RANKL шляхом дифузії впливають на остеоцити.…”