Abstract
ObjectiveSubchondral bone modifications occur early in the development of osteoarthritis (OA). The level of bone resorption might impact cartilage remodeling. We therefore assessed the in vivo and in vitro effects of targeting bone resorption in OA and cartilage metabolism.MethodsOA was induced by meniscectomy (MNX) in ovariectomized osteopenic mice (OP) treated with estradiol (E2), pamidronate (PAM), or phosphate buffered saline (PBS) for 6 weeks. We assessed the subchondral bone and cartilage structure and the expression of cartilage matrix proteases. To assess the involvement of bone soluble factors in cartilage metabolism, supernatant of human bone explants pre-treated with E2 or PAM were transferred to cartilage explants to assess proteoglycan release and aggrecan cleavage. OPG/RANKL mRNA expression was assessed in bone explants by real-time quantitative PCR. The role of osteoprotegerin (OPG) in the bone-cartilage crosstalk was tested using an OPG neutralizing antibody.ResultsBone mineral density of OP mice and osteoclast number were restored by E2 and PAM (p<0.05). In OP mice, E2 and PAM decreased ADAMTS-4 and -5 expression, while only PAM markedly reduced OA compared to PBS (2.0±0.63 vs 5.2±0.95; p<0.05). OPG/RANKL mRNA was increased in human bone explants treated with both drugs (2.2–3.7-fold). Moreover, supernatants from bone explants cultured with E2 or PAM reduced aggrecan cleavage and cartilage proteoglycan release (73±8.0% and 80±22% of control, respectively, p<0.05). This effect was reversed with osteoprotegerin blockade.ConclusionThe inhibition of bone resorption by pamidronate in osteopenic mice alleviates the histological OA score with a reduction in the expression of aggrecanases. Bone soluble factors, such as osteoprotegerin, impact the cartilage response to catabolic factors. This study further highlights the importance of subchondral bone in the regulation of joint cartilage damage in OA.
Highlights
Osteoarthritis (OA) is a common disease responsible for high morbidity related to functional disability and pain
Inhibitors of bone resorption restore subchondral bone architecture in osteopenic mice (OP) mice The bodyweight of mice remained stable in each group throughout the study (Table 1)
Uterus weight declined after ovariectomy in the Phosphate Buffered Saline (PBS)-treated and Pamidronate (PAM)-treated mice, but was maintained in the mice treated with estradiol
Summary
Osteoarthritis (OA) is a common disease responsible for high morbidity related to functional disability and pain. Subchondral bone lesions appear during the early stages of OA, as demonstrated by the presence of bone marrow lesions that are factors predictive of OA progression [4,5]. The natures of such bone lesions are still poorly established, trabecular fractures or enhanced trabecular bone remodeling are suspected. Stages of OA are accompanied by a decrease in bone volume, which suggests that initial bone resorption might trigger OA [6,7,8,9]. Reducing bone remodeling in Runx transgenic mice prevents from cartilage breakdown [12]
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