Estrogen replacement therapy mitigates the loss of joint cartilage proteoglycans and bone mineral density induced by ovariectomy and osteoarthritis

Abstract

Aims: To investigate the effects of ovariectomy and estrogen replacement therapy (ERT) on the structural integrity and proteoglycan (PG) content of articular cartilage (AC) and bone mineral density (BMD) in an ovine model of osteoarthritis (OA) induced by meniscectomy. Method: Thirty aged ewes were used for the study. Six had ovariectomy alone (OVX), 6 meniscectomy alone (OA) and 12 ovariectomy and meniscectomy (OVX + OA). Six of the (OVX + OA) sheep received Femtran‐50 (3M) estrogen (50 µg/day) patches (OVX + OA + ERT). Six animals were used as non‐operated controls (NOC). Three months post‐surgery all animals were sacrificed, the stifle joints dissected through the site of lesions, and coronal sections of the lateral femoral condyle (LFC) and lateral tibial plateau (LTP) were cut which were each subdivided into inner (I), middle (M) and outer (O) zones. Toluidine blue stained sections were examined using a modified Mankin scoring system, and AC–PG content determined via computer image analysis. Results: There were no significant differences between lesion scores among the OA, OVX + OA and OVX + OA + ERT groups, yet all had significantly higher scores than NOC and OVX in each region (P < 0.005). Computer image analysis of PG content in stained sections showed no difference between OVX and NOC. However, in LFC‐AC the loss of PG was highest in the OVX + OA group (P < 0.005) compared to the NOC or OVX groups. The bone mineral density (BMD) of the LFC averaged for all zones was higher in the OVX + OA + ERT group than the OVX + OA group (P < 0.02) with the most significant rise being in the I‐zone (P < 0.002). Significantly in this same zone of the OVX + OA + ERT group the AC‐PG content was higher than in the corresponding zone of the OVX + OA group (P < 0.05). Conclusions: While ERT did not reduce the focal AC lesions scores in the lateral compartment of this OA model it did mitigate the loss of PG from adjacent joint cartilage and increase the bone mineral density (BMD), especially in the I‐zone. These findings are consistent with epidemiological studies which suggest that ERT may slow the progression of OA in postmenopausal women.

Estradiol inhibits chondrogenic differentiation of mesenchymal stem cells via nonclassic signaling

“…Female patients have been shown to have a significantly higher prevalence of OA after estrogen decline during menopause as compared with male patients during the same time frame (8, 9). Accordingly, further studies demonstrated reduced loss of articular cartilage in postmenopausal women who received estrogen replacement therapy (ERT) (10, 11). However, the effects of ERT are still not understood since results have been conflicting (12).…”

Estrogen modulates iodoacetate‐induced gene expression in bovine cartilage explants

“…The possible beneficial effects of estrogen on cartilage is seen in several animal models, in which induction of OA is combined with ovariectomy and/or with estrogen replacement therapy 44–46. However, in these in vivo models, other tissues in the joint, such as bone, synovium, ligament, and muscle may contribute the OA protective effects of estrogen, as these tissues also express estrogen receptors 11, 12, 47–49.…”

Examination of osteoarthritis and subchondral bone alterations within the stifle joint of an ovariectomised ovine model

“…; Parker et al. ; Little & Smith, ). There are a number of methods by which an injury may be induced, and it has been suggested that the subchondral changes observed at 12 weeks are quite different depending on the exact type of insult used (Kuroki et al.…”

“…The ovine stifle joint is frequently employed in these studies as it may be considered to be a 1 : 3 scale model of the human knee joint (Osterhoff et al 2011). Osteoarthritis is typically induced by means of an experimental injury; monoarticular studies may do this by causing an injury to an articular structure in order to destabilise the joint, or by placing the joint under abnormal mechanical loading (Pritzker, 1994;Hwa et al 2001;Parker et al 2003;Little & Smith, 2008). There are a number of methods by which an injury may be induced, and it has been suggested that the subchondral changes observed at 12 weeks are quite different depending on the exact type of insult used (Kuroki et al 2011).…”

“…There are a number of methods by which an injury may be induced, and it has been suggested that the subchondral changes observed at 12 weeks are quite different depending on the exact type of insult used (Kuroki et al 2011). Within the ovine model, meniscectomy has proven to be most reliable (Little et al 1997;Hwa et al 2001;Parker et al 2003).…”