Effect of Selective Estrogen Receptor Modulator/Raloxifene Analogue on Proliferation and Collagen Metabolism of Tendon Fibroblast

Abstract

The selective estrogen receptor modulator raloxifene is therapeutically beneficial for postmenopausal connective tissue degradation, such as osteoporosis, vascular sclerosis, and dermal degradation; however, the effects of raloxifene on postmenopausal tendon metabolism have not been clarified. In this study, we investigated the effects of raloxifene analogue (LY117018) on cell proliferation and collagen metabolism using cultured rat Achilles tendon fibroblasts. 17beta-Estradiol (E(2); 10(-11)-10(-9) M) and LY117018 (10(-9)-10(-7) M) had no significant effects on tendon fibroblast proliferation, based on a BrdU (5-bromo-2'-deoxyuridine) incorporation assay (24 hr) and a WST-8 colorimetric assay (2 or 6 days). Neither E(2) nor LY117018 significantly altered the expression of type I collagen, which is a main component of the tendon extracellular matrix (ECM), whereas both E(2) and LY117018 significantly increased the expression of matrix metalloproteinase (MMP)-13, which is responsible for tendon collagen degradation in rat. Also, both E(2) and LY117018 increased the expression of type III collagen and elastin, which are minor components of tendon ECM, but are considered to govern the elastic properties of tendons. These changes in collagen and MMP induced by either E(2) or LY117018 were attenuated by the estrogen receptor alpha blocker ICI 182,780. The results of this study suggest that postmenopausal estrogen deficiency might downregulate tendon collagen turnover and decrease tendon elasticity. Further, raloxifene treatment might restore these changes to premenopausal levels.

Estrogen improves TIMP-MMP balance and collagen distribution in volume-overloaded hearts of ovariectomized females

“…The increase of collagen type III in response to estrogen administration was found in hearts of aged and Dahl salt-sensitive rats (8,61). Similar estrogenic effects on collagen III were demonstrated in the arteries and other tissues of ovariectomized animals (7,10,15,24,36,47). The mechanisms of enhanced collagen type III expression due to estrogen treatment are still unknown, but they are likely related to the changes in MMPs and TIMPs expression that we Fig.…”

Characteristics and Stimulation Potential with BMP-2 and BMP-7 of Tenocyte-Like Cells Isolated from the Rotator Cuff of Female Donors

“…It has been reported that tenocytes of the posterior tibial tendon and flexor digitorum longus tendon of male and female donors express estrogen receptors, which are activated by estrogens such as estradiol [42]. Moreover, it has been found that estradiol had an effect on tendon fibroblasts by increasing Col-III and elastin expression [43], and inhibiting proliferation, and Col-I synthesis [44], when the hormone was directly added to the cell cultures. The influence of estrogens has also been shown in vivo, with the finding that collagen synthesis decreases in women with a higher hormone status [12], [45].…”

In vitro tenocyte metabolism in aging and oestrogen deficiency

“…In addition to aging, oestrogen levels might also play a key role, as observed in women that show a lower risk of tendinopathies during pre-menopausal years, whereas, after menopause, this risk increases (Tsai et al 2011). Oestrogen levels (Irie et al 2010) may influence tendon metabolism, and, in addition to several growth factors (i.e. platelet-derived growth factor, transforming growth factor-β, insulin growth factor-1, vascular endothelial growth factor, bone morphogenetic proteins, growth differentiation factors), oestrogens are important for the behaviour of musculoskeletal tissues and may affect tendon properties; postmenopausal oestrogen deficiency seems to downregulate collagen turnover and to decrease elasticity in tendon (Circi et al 2009).…”