The expression of RANKL and OPG in the various grades of osteoarthritic cartilage

Abstract

The objective of the study was to determine whether cartilage expression of the bone regulating molecules receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) varies between the different grades of osteoarthritis (OA). Cartilage samples were obtained from 30 patients undergoing total hip/knee replacement surgery. Tissue sections were stained with Safranin O and graded. Immunohistochemical staining was then performed, and levels of RANKL and OPG expression were assessed using a semi-quantitative scoring system. In addition, levels of mRNA encoding for RANKL and OPG were determined by a relative real-time reverse transcription-polymerase chain reaction technique. We found that expression of RANKL protein, mRNA expression, and the ratio of RANKL: OPG mRNA was greater in grade 2 cartilage in comparison with grade 0 cartilage (P < 0.05). Increased RANKL staining in the grade 2 cartilage was predominantly in the peri-cellular region of the middle and deep zones as well as in the matrix of the superficial zone. OPG mRNA expression was greater in grade 3 cartilage in comparison with grade 0 cartilage (P < 0.05). Cartilage and subchondral bone are in close proximity and soluble proteins produced in the cartilage are likely to move from one compartment to the other. Our finding of increased expression of RANKL in grade 2 OA cartilage might explain the increase in bone turnover reported in the subchondral bone of OA patients. The changes seen in the different grades of tissue may also indicate that this effect occurs during the early stages of OA development.

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

“…Changes in subchondral bone turnover precede changes in cartilage (see references in Kwan Tat et al 9) and pain-related molecules have been detected in OA subchondral bone 10. Dynamic changes in bone turnover result from increased activity of osteoclasts and osteoblasts, and the osteoprotegerin (OPG)/receptor activator of NF-κB (RANK)/receptor activator of NF-κB ligand (RANKL) system is critical for this activity 9 11 12. Osteoclast activation is associated with reduced extracellular pH, and release of proteases.…”

“…An imbalance in the OPG/RANKL system, both in synovial fluid and serum, has been associated with OA severity in man 12 23. Exogenous treatment with a modified OPG (OPG-Fc) attenuates bone loss in a rodent model of inflammatory arthritis24 and, although effects on arthritis pain were not reported, OPG inhibited bone cancer-induced pain behaviour 25.…”

Increased receptor activator of nuclear factor κβ ligand/osteoprotegerin ratio exacerbates cartilage destruction in osteoarthritis in vitro

“…MMP-13 is predominantly localized in the deeper layers of cartilage (29). In a study performed by Upton et al (30), increased RANKL mRNA expression levels were observed in grade II OA cartilage, particularly in the deep layer of cartilage. Various previous studies have reported that RANKL is expressed by chondrocytes in normal and OA cartilage (12,31).…”

“…A previous biochemical analysis of the circulating levels of macromolecules released from cartilage and bone in humans revealed a convergence of the pathological processes in cartilage and subchondral bone in OA at each stage (6). Furthermore, a previous study demonstrated that RANKL secreted by chondrocytes diffuse across the thin layer of calcified cartilage into subchondral bone, resulting in morphological changes to subchondral bone, which is an important factor in OA pathophysiology (30). Combined with the results of the present study, we hypothesize that RANKL overexpression in subchondral bone may diffuse into cartilage and elevate MMP-13 expression levels, which subsequently accelerates cartilage degradation.…”

Pathogenesis of Osteoarthritis and Substantiation of the Use of Strontium Ranelate

“…Большинство авторов признают, что ключевую роль в регуляции метаболизма костных клеток играет молекуляр-ная триада: остеопротегерин / рецептор, активирующий фактор транскрипции NFκB / лиганд этого рецептора (ОPG/RANK/RANKL) [22]. Одним из факторов, регулиру-ющих функционирование данной триады, является уро-вень половых гормонов.…”