Targeting Bone Alleviates Osteoarthritis in Osteopenic Mice and Modulates Cartilage Catabolism
Open Access
- 14 March 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (3), e33543
- https://doi.org/10.1371/journal.pone.0033543
Abstract
Subchondral 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. OA 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. Bone 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. The 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.This publication has 39 references indexed in Scilit:
- Subchondral Cystlike Lesions Develop Longitudinally in Areas of Bone Marrow Edema–like Lesions in Patients with or at Risk for Knee Osteoarthritis: Detection with MR Imaging—The MOST StudyRadiology, 2010
- Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosisArthritis Research & Therapy, 2010
- Osteoarthritis associated with estrogen deficiencyArthritis Research & Therapy, 2009
- Change in MRI-detected subchondral bone marrow lesions is associated with cartilage loss: the MOST Study. A longitudinal multicentre study of knee osteoarthritisAnnals Of The Rheumatic Diseases, 2008
- Osteoprotegerin inhibits cartilage degradation through an effect on trabecular bone in murine experimental osteoarthritisArthritis & Rheumatism, 2008
- Prevention of cartilage destruction with intraarticular osteoclastogenesis inhibitory factor/osteoprotegerin in a murine model of osteoarthritisArthritis & Rheumatism, 2007
- Estrogen receptor alpha genotype is associated with a reduced prevalence of radiographic hip osteoarthritis in elderly Caucasian womenOsteoarthritis and Cartilage, 2007
- Oestrogens inhibit interleukin 1 -mediated nitric oxide synthase expression in articular chondrocytes through nuclear factor- B impairmentAnnals Of The Rheumatic Diseases, 2007
- Estrogen receptor α gene haplotype is associated with radiographic osteoarthritis of the knee in elderly men and womenArthritis & Rheumatism, 2003
- Expression of genes for estrogen receptors α and β in human articular chondrocytesOsteoarthritis and Cartilage, 1999