Raloxifene ameliorates cartilage and subchondral bone microstructural degeneration in the ovariectomy-induced spontaneous postmenopausal osteoarthritis

The prevalence and incidence of osteoarthritis (OA) increase significantly in women after menopause, indicating an important role of estrogen in the pathogenesis of OA. This type of OA is termed postmenopausal OA. This study aimed to investigate the feasibility of using bilateral ovariectomy (OVX) in adult SD rats to simulate the human postmenopausal OA model and evaluate the effect of early raloxifene (RAL) intervention on this model. Twenty-four SD rats were randomly divided into 4 groups: Baseline group, Sham + V group, OVX + V group, and OVX + RAL group. Rats in the Baseline group were euthanized for sample collection at the start of the experiment. Rats in the OVX + V and OVX + RAL groups underwent bilateral OVX, while those in the Sham + V group received a sham operation without actual ovarian resection. After surgery, the OVX + RAL group was given RAL (6.2 mg/kg·day) by gavage, and the OVX + V and Sham + V groups received an equal volume of normal saline. Samples were collected 3 months after drug administration. Micro-CT was used to determine the bone histomorphometry of the right proximal tibia. Following Micro-CT analysis, the right knee joints of all animals were decalcified for 8–12 weeks, embedded in paraffin, and sectioned. The sections were subjected to toluidine blue staining and immunohistochemical staining for collagen-II, Caspase-3, and matrix metalloproteinase-13 (MMP-13). The toluidine blue-stained sections were scored using the OARSI histological scoring system, and the positive protein expression in immunohistochemical staining was evaluated using the IOD. The OARSI score revealed that the degree of cartilage degeneration in the OVX + V group was more severe than that in the Sham + V group and the OVX + RAL group. The expression of collagen-II in the OVX + V group was significantly lower than that in the Sham + V group and the OVX + RAL group, while the expressions of MMP-13 and Caspase-3 increased. Micro-CT revealed that the microstructure of subchondral bone in the OVX + V group deteriorated compared with the Sham + V group, while that in the OVX + RAL group improved compared with the OVX + V group. Compared with the Baseline group, the microstructure of subchondral bone and cartilage in the Sham + V group was somewhat degraded. We reached a conclusion that OVX-induced degeneration of subchondral bone and articular cartilage is relatively mild, suggesting that 6-month-old OVX rats are a mild model of postmenopausal OA. RAL can delay OVX-induced postmenopausal subchondral bone and cartilage degeneration. Notably, this study further clarifies the protective effect of RAL on the medial joint capsule and refines the regulatory mechanism of RAL on subchondral bone microstructure in mild postmenopausal OA, which supplements the existing research on RAL in OA intervention.