Targeting Bone Alleviates Osteoarthritis in Osteopenic Mice and Modulates Cartilage Catabolism

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.

Effects of Bisphosphonate on the Expression of Matrix Enzymes during Endochondral Ossification

“…One is the inhibitory role of chondroclasts, cartilage resorbing cells [9] and the other is regulation of matrix enzymes such as MMPs and TIMPs involved in resorption of cartilage [21,22]. From the beginning, the present study proposed that bisphosphonates might induce changes of cartilaginous matrix by regulating enzymes involved in these changes on the basis of the previous reports that these chemicals were implicated with bone resorption [23,24].…”

Subchondral bone and osteoarthritis

“…Most of these models are consistent and report an early increase in bone resorption followed in later stages with an increase in formation [43]. Moreover, the level of bone remodeling could directly impact the severity of cartilage degeneration, as shown in various models of osteoarthritis with ovariectomy [44], use of glucocorticosteroids and ovariectomy [45], or in genetically modified mice [46]. Altogether, these studies suggest the pathogenic role of an increased cellular activity in the subchondral bone involving osteoclasts in early stages followed by osteoblasts/osteocytes in later stages.…”

Animal models of osteoarthritis for the understanding of the bone contribution

“…34 Moreover, inhibition of resorption in mice with high bone remodeling results in a reduction of cartilage lesions. 35,36 Interestingly, collagenaseinduced OA results in changes in the trabecular network and promotes osteoclastogenesis, 37 confirming an early high bone resorption at early stages of OA regardless of whether the initial stress is mechanical or chemical. Altogether, the acceleration of bone remodeling might be an initial step, followed by the thickening of subchondral bone, which might be an adaptive response secondary to mechanical loading or an attempt to repair the cartilage.…”