Osteoarthritic cartilage damage is aggravated by ovariectomy plus glucocorticoid-induced osteoporosis in a rabbit model. Ovariectomy itself induces small disturbances in the cartilage, while no differences were found between articular cartilage from ovariectomized (OVX), osteoporosis (OP) and osteoarthritis (OA) rabbits. Bar graphs showing the total Mankin score from the histological evaluation of joint cartilage at the weight bearing area of the medial femoral chondyle in the different experimental groups. Healthy, controls; OVX, ovariectomized rabbits; OP, osteoporotic rabbits induced by OVX followed by parenteral methyprednisolone injections for 4 weeks; OA, osteoarthritic rabbits induced by partial medial meniscectomy and anterior cruciate ligament section of the knee; OP+OA, rabbits with experimentally induced OP followed by OA induction. Data are expressed as the mean ± standard deviation. ^#P < 0.05 versus healthy; ^&P < 0.05 versus OVX; ^§P < 0.05 versus OP; ^¶P < 0.05 versus OA.

Structural composition of estrogen receptor (ER)α and ERβ. Both receptors have four functional domains that harbor a DNA-binding domain (DBD), a ligand-binding domain (LBD) and two transcriptional activation functions (AF-1 and AF-2), as indicated for ERβ. The percent of homology in these domains between ERα and ERβ is indicated, as well as the location of several phosphorylation sites in ERα whereby this receptor is activated by important kinases that modulate a wide variety of cellular events. aa, amino acids; Akt, serine/threonine specific-protein kinase family encoded by the Akt genes; CDK2, cyclin-dependent kinase 2; MAPK, mitogen activated protein kinase; PKA, protein kinase A; Src: steroid receptor coactivator.

Estrogen actions on target articular tissues. ACL, anterior cruciate ligament; [Ca2+]i, intracellular calcium concentration; COX-2, cyclooxygenase-2; IGF, insulin-like growth factor; iNOS, inducible nitric oxide synthase; MRI, magnetic resonance imaging; OB, osteoblast; OVX, ovariectomized; PG, proteoglycan.

Intracellular signaling pathways used to regulate the activity of estrogens, estrogen receptors, and selective estrogen receptor modulators on articular tissues. Pathway 1: canonical estrogen signaling pathway (estrogen response element (ERE)-dependent) - ligand-activated estrogen receptors (ERs) bind specifically to EREs in the promoter of target genes. Pathway 2: non-ERE estrogen signaling pathway - ligand-bound ERs interact with other transcription factors, such as activator protein (AP)-1, NF-κB and Sp1, forming complexes that mediate the transcription of genes whose promoters do not harbor EREs. Co-regulator molecules regulate the activity of the transcriptional complexes. Pathway 3: non-genomic estrogen signaling pathways - ERs and GP30 localized at or near the cell membrane might elicit the rapid response by activating the phosphatidylinositol-3/Akt (PI3K/Akt) and/or protein kinase C/mitogen activated protein kinase (PKC/MAPK) signal transduction pathways. Pathway 4: ligand-independent pathways - ERs can be stimulated by growth factors such as insulin-like growth factor (IGF)-1, transforming growth factor-β/mothers against decapentaplegic (TGF-β/SMAD), epidermal growth factor (EGF) and the Wnt/β-catenin signaling pathway in the absence of ligands, either by direct interaction or by MAP and PI3/Akt kinase-mediated phosphorylation. Since members of these signaling pathways are transcription factors, some of them, such as SMADs 3/4, can elicit estrogen responses by interacting with ER in the non-ERE-dependent genomic pathway. ERK, extracellular signal regulated kinase; GF, growth factor; GFR, growth factor receptor; MNAR, Modulator of nongenomic action of estrogen receptors; TF, transcription factor.