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      Estrogen Modulates Cartilage and Subchondral Bone Remodeling in an Ovariectomized Rat Model of Postmenopausal Osteoarthritis

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          Abstract

          Background

          Estrogen levels regulate changes in osteoarthritis (OA) by inhibiting degradation of the extracellular matrix. Recent in vitro studies have also shown the role of microRNA-140-5p (miR-140-5p). This study aimed to investigate the role of estrogen deficiency, selective modulation of expression of the estrogen receptor (ER), and expression of miR-140-5p in cartilage and subchondral bone remodeling in an ovariectomized rat model of postmenopausal OA.

          Material/Methods

          Female Sprague-Dawley rats included two model groups, ovariectomized (OVX) rats and rats with destabilization of the medial meniscus (DMM) rats. Two months after surgery, estrogen levels were measured by the enzyme-linked immunosorbent assay (ELISA). Three-dimensional (3D) micro-computed tomography (micro-CT) was used to image the knee joints. Rats were treated with subcutaneous injection of estrogen (E2) or the selective estrogen receptor modulator (SERM), raloxifene (RAL), for one month. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect miR-140-5p in serum, and histology of the knee joint cartilage and bone was performed.

          Results

          In the ovariectomized rat model of OA, estrogen therapy reduced the degree of cartilaginous degeneration, while treatment with raloxifene showed no significant effect. Expression levels of miR-140-5p in the OA model group were significantly lower than the control group. Micro-CT showed that in the model group, anterior cruciate ligament dislocation and subchondral bone density were significantly reduced.

          Conclusions

          In an ovariectomized rat model of postmenopausal OA, estrogen deficiency resulted in resorption of subchondral bone and degeneration of articular cartilage.

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          Most cited references 11

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          Osteoarthritis severity is sex dependent in a surgical mouse model.

          To investigate the role of sex hormones in cartilage degradation and progression of osteoarthritis (OA) in a murine model induced by destabilization of the medial meniscus (DMM). Accelerated OA development in mice was induced by transection of the menisco-tibial ligament, which anchors the medial meniscus to the tibial plateau. Intact male and female, and orchiectomized (ORX) male and ovariectomized (OVX) female mouse knee histology were compared for signs of OA following DMM. The effect of testosterone or estrogen addition in vivo was assessed in ORX males in the surgical OA model. OA severity was markedly higher in males than females after DMM. OVX females developed significantly more severe OA than control females. ORX males developed significantly less severe OA than control males. When ORX male mice were supplemented with exogenous dihydrotestosterone (DHT), the severity of OA was restored to the level experienced by the control male mice. Hip cartilage from mice of both sexes demonstrated similar spontaneous and interleukin-1alpha (IL-1alpha) induced proteoglycan (PG) release in vitro. DHT and 17-beta estradiol (E2) did not significantly alter the PG release pattern when supplemented to cartilage cultures of either sex. Sex hormones play a critical role in the progression of OA in the murine DMM surgical model, with males having more severe OA than females. Intact females had more OA than OVX females, indicating that ovarian hormones decrease the severity of OA in the female mice. Male hormones, such as testosterone, exacerbate OA in male mice as demonstrated by the fact that ORX mice experienced less OA than intact males, and that addition of DHT to ORX males was able to counteract the effect of castration and re-establish severe OA.
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            Composition and dynamics of articular cartilage: structure, function, and maintaining healthy state.

            Disorders of articular cartilage represent some of the most common and debilitating diseases encountered in orthopaedic practice. Understanding the normal functioning of articular cartilage is a prerequisite to understanding its pathologic processes. The mechanical properties of articular cartilage arise from the complex structure and interactions of its biochemical constituents: mostly water, electrolytes, and a solid matrix composed primarily of collagen and proteoglycan. The viscoelastic properties of cartilage, due primarily to fluid flow through the solid matrix, can explain much of the deformational responses observed under many loading conditions. Degenerative processes can often be explained by a breakdown of the normal load-bearing capacity of cartilage which arises from the mechanics of this fluid flow. Several factors which may lead to such a breakdown include direct trauma to the cartilage, obesity, immobilization, and excessive repetitive loading of the cartilage. Sports activity, without traumatic injury, does not appear to be a risk factor for the development of osteoarthritis in the normal joint; however, such activity may be harmful to an abnormal joint.
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              Evidence for increased bone resorption in patients with progressive knee osteoarthritis: longitudinal results from the Chingford study.

              Several studies have suggested that increased subchondral bone turnover is a determinant of progression of osteoarthritis (OA). To test this hypothesis, the level of urinary N-terminal type I collagen telopeptides (NTx) and C-terminal type I collagen telopeptides (CTx), which are validated markers of bone resorption, was measured at 3 different time points in a subset of patients from the Chingford study. The original Chingford study population comprised 1,003 women. From this group, postmenopausal women not receiving any bone-modifying medication who had a baseline knee radiograph and a repeat radiograph 4 years later, and for whom a baseline lumbar spine bone mineral density (BMD) measurement was available, were identified and separated into 4 groups as follows: controls (n = 50), progressive OA (n = 71), nonprogressive OA (n = 36), and osteoporosis (n = 59). NTx and CTx were measured in urine samples collected at baseline, year 1, and year 2. Patient age and years since menopause were similar among groups at baseline. As expected, both body mass index (BMI) and BMD were lowest in patients with osteoporosis. Median resorption marker levels over the 3 time points were 31-87% higher in patients with either progressive OA or osteoporosis than in controls and patients with nonprogressive OA (P < 0.01, except for levels of CTx in patients with progressive OA versus nonprogressive OA). Levels of NTx and CTx did not differ significantly between women with progressive OA (defined either by the presence of osteophytes or by joint space narrowing) and those with osteoporosis or between controls and women with nonprogressive OA. Results were essentially unchanged after adjustment for age, BMI, BMD, and past use of hormone replacement therapy, or when NTx and CTx values at each time point were analyzed separately. Our data demonstrate that bone resorption is increased in patients with progressive knee OA and is not increased in those with nonprogressive knee OA. The increase in bone resorption seen in patients with progressive knee OA is similar to that observed in patients with osteoporosis. Altered bone turnover may be a diagnostic or therapeutic target in patients with progressive OA.
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                Author and article information

                Journal
                Med Sci Monit
                Med. Sci. Monit
                Medical Science Monitor
                Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
                International Scientific Literature, Inc.
                1234-1010
                1643-3750
                2019
                29 April 2019
                : 25
                : 3146-3153
                Affiliations
                [1 ]Guangzhou Medical University, Guangzhou, Guangdong, P.R. China
                [2 ]Shenzhen Key Laboratory of Tissue Engineering, Shenzhen Laboratory of Digital Orthopedics Engineering, Department of Orthopedics, Shenzhen Second Peoples’ Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong, P.R. China
                [3 ]Guangdong Provincial Research Center for Artificial Intelligence and Digital Orthopedic Technology, Shenzhen, Guangdong, P.R. China
                [4 ]Shantou University Medical College, Shantou, Guangdong, P.R. China
                [5 ]Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, P.R. China
                [6 ]Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, P.R. China
                Author notes
                Corresponding Authors: Li Duan, e-mail: 825343512@ 123456qq.com , Daping Wang, e-mail: dapingwang1963@ 123456qq.com
                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                [*]

                Xiao Xu and Xingfu Li contributed equally to this work

                Article
                916254
                10.12659/MSM.916254
                6503753
                31031401
                © Med Sci Monit, 2019

                This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International ( CC BY-NC-ND 4.0)

                Categories
                Animal Study

                estrogens, micrornas, osteoarthritis, raloxifene

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