Chondroitin may positively affect osteoarthritic subchondral bone
Chondroitin sulfate increases ratio of osteoprotegerin to RANK ligand in human osteoarthritic subchondral bone osteoblasts.
Chondroitin sulfate appears to exert a positive effect on osteoarthritis at the level of the subchondral bone, offering a possible explanation of how this agent has a positive effect on the progression of osteoarthritic articular structural changes.
This effect needs to be better understood in order to determine whether chondroitin sulfate could be an effective agent to halt the effects of osteoarthritis.
The progression of osteoarthritis could be divided into three broad stages. In stage 1, there is proteolytic activity resulting in breakdown of the cartilage matrix.
Stage 2 involves fibrillation and erosion of the cartilage surface, accompanied by release of breakdown products into the synovial fluid.
During stage 3, there is synovial inflammation resulting from the ingestion by the synovial cells of breakdown products leading to the production of proteases and proinflammatory cytokines.
A growing amount of evidence suggests that alteration in osteoarthritis also involves the subchondral bone (Figure).1,2
This alteration could be the driving force behind cartilage degradation and loss, as an association exists between increased subchondral bone remodeling and the development of cartilage lesions.
Source: Martel-Pelletier J
Some continuity between the subchondral bone and cartilage during osteoarthritis exists, suggesting a cross talk between the two tissues. Questions remain, however, whether changes in the subchondral bone induce or participate in the progression of osteoarthritis.
We undertook a study to look at the effect of chondroitin sulfate on the expression and production of major osteoblast factors involved in the remodeling of subchondral bone.
Data from our laboratory showed that the subchondral bone osteoblasts have an altered metabolism, causing elevated levels of alkaline phosphatase and osteocalcin.1
We investigated on human subchondral bone osteoblasts the effect of 200 µg/mL of chondroitin sulfate before and after vitamin D3 stimulation on a number of factors, including osteoprotegerin (OPG) and the RANK ligand (RANKL).
RANKL is synthesized by osteoblasts and plays an essential role in osteoclast differentiation and bone loss. OPG is a decoy receptor that blocks the binding of RANKL to RANK thereby preventing RANK activation and osteoclastogenesis, thus inhibiting bone resorption.
The OPG/RANKL ratio is considered a key regulator of bone metabolism. We recently found that in osteoarthritic subchondral bone osteoblasts, OPG and RANKL are altered when compared to normal.3
Chondroitin sulfate effects
Chondroitin sulfate did not overly affect cell integrity or osteoblast phenotypic cell markers but could positively affect tissue inflammation as COX-2 level is reduced.
Chondroitin sulfate had a marked effect on the OPG and RANKL system by increasing OPG protein synthesis in the absence or presence of vitamin D3. The expression of basal OPG was reduced by chondroitin sulfate, however. Vitamin D3 also reduces OPG expression level, but chondroitin sulfate in the presence of vitamin D3 reverses this effect.
The differential effect of chondroitin sulfate under basal conditions between OPG expression and synthesis could be due to stabilization of OPG mRNA by chondroitin sulfate.
Chondroitin sulfate significantly inhibited RANKL expression under basal conditions. This has clinical implications as RANKL expression increases in osteoarthritic osteoblasts, weighing the balance of OPG/RANKL toward bone destruction.
Chondroitin sulfate also increased the OPG/RANKL ratio,indicating that chondroitin sulfate could exert a positive effect on osteoarthritis structural changes at the level of subchondral bone.
Evidence that the OPG-RANKL ratio is increased by chondroitin sulfate in human subchondral bone osteoblasts is of major significance as bone resorption could be dictated by the ratio of OPG/RANKL.
- Hilal G, Martel-Pelletier J, Pelletier JP, et al. Osteoblast-like cells from human subchondral osteoarthritic bone demonstrate an altered phenotype in vitro: possible role in subchondral bone sclerosis. Arthritis Rheum. 1998;41:891-899.
- Hilal G, Martel-Pelletier J, Pelletier JP, et al. Abnormal regulation of urokinase plasminogen activator by insulin-like growth factor 1 in human osteoarthritic subchondral osteoblasts. Arthritis Rheum. 1999;42:2112-2122.
- Martel-Pelletier J, Lajeunesse D, Mineau F, et al. The differential expression of OPG/RANKL in human osteoarthritic subchondral bone osteoblasts is an indicator of the metabolic state of these disease cells. Arthritis Rheum. 2005;52:S496 (abstract).