Table 2 Impact of sex hormones on cartilage regeneration
From: Sex-dependent variation in cartilage adaptation: from degeneration to regeneration
Hormones | Study design | Treatment | Analysis | Results | Implications | References |
|---|---|---|---|---|---|---|
T/DHT | In vitro; murine ESCs | Cultured with T, DHT, or NT at each of the following concentrations: 10–6 M, 10–8 M, and 10–10 M in ethanol | IHC for androgen receptor, qPCR, cell colorimetric assays, Western blot | T had no significant effects on proliferation, while DHT marginally inhibited proliferation of ESCs; NT significantly increased ESC proliferation | ESC proliferation from blastocyst is independent of androgen effects | [207] |
T | In vitro; human IVD cells and BMSCs | Differentiation in the presence or absence of T (10Â ng/mL) | PCR, immunoblotting, IHC | Male IVD cells exposed to T exhibited increased aggrecan and types I and II collagen expression compared to control; T had no effect on female IVD cell chondrogenesis or BMSC chondrocytes from either sex | T increases ECM production in male IVD cells during differentiation | [92] |
In vivo; male rabbit growth plate chondrocytes | ORX versus non-ORX male rabbits | Soft radiography, IHC, quantification of caspase-3 and PCNA expression | At weeks 8–15 for ORX group, proliferation was decreased in quantity and displayed a narrowed proliferating zone compared to control | T accelerates growth and maturation of the epiphyseal plate and stimulates proliferation in males | [206] | |
In vitro; rat costochondral growth zone and resting zone chondrocytes | Incubation with various doses of T: 10,100, and 1000Â ng/mL | Thymidine incorporation, cell quantity, ALP activity, and collagen production | T inhibited cell number and dose-dependent decrease in thymidine incorporation of male growth zone and resting zone chondrocytes; cell quantity and thymidine incorporation unaffected by T in female rat cells; only significant change in ALP activity was an increase in ALP activity in T-treated growth zone male chondrocytes; T stimulated production of collagen in male growth zone and resting zone chondrocytes but T did not affect female cell collagen production | T primarily influences male chondrocytes and induces osteoblastic and chondrogenic differentiation | [197] | |
In vivo; human patients with severe knee OA | Unilateral TKR | Serum T levels, knee radiograph, and WOMAC pain/function analysis 6–8 weeks after surgery | On the operative knee, higher T levels were associated with less pain in both sexes; in the non-operative knee, higher T in women was associated with less disability | T is positively correlated with less pain after TKR in both sexes and less disability in women without TKR | [196] | |
E2 | In vitro; human ASCs | Cultured with E2 (concentration of 10–8 M) or without E2 | RT-PCR | E2 exposure led to inhibition of COL2A1 expression and reduction of ACAN expression | E2 may have a negative impact on human ASC chondrogenesis | [216] |
In vitro; human BMSCs | Cultured with E2 (concentrations ranging from 10–11 M to 10–8 M) with or without ER inhibitor | Histology, IHC, quantification of type II collagen, sulfated GAGs, type X collagen, and MMP13 | E2 treatment resulted in a reduction of type II collagen and enhancement of type X collagen and MMP13 expression | E2 suppresses chondrogenesis of human BMSCs | [215] | |
In vitro; murine ESCs | Incubated in E2 (0–10−6 M for 8 h) or at 10–9 M for times ranging from 0 to 12 h | ALP staining, immunofluorescence, thymidine incorporation, BrdU incorporation, RT-PCR, Western blot | E2 treatment significantly increased thymidine incorporation, BrdU incorporation, and cell number | E2 stimulates proliferation of mouse ESCs | [208] | |
In vitro; mini-pig BMSCs | Cultured in E2 at 0 M, 10–6 M, 10–8 M, 10–10 M, 10–12 M, or 10–14 M | Surface marker analysis, ALP, MTT proliferation assay, β-galactosidase staining, TUNEL staining, differentiation/cytochemical staining, RT-PCR | E2 increased proliferation in female BMSCs, with a dose of 10–12 M optimizing proliferation. E2 also increased proliferation in male cells to a lesser degree that is still significant; E2 at 10–12 M inhibited cellular senescence in BMSCs from both sexes; E2 did not significantly influence chondrogenic differentiation; E2 increased adipogenic differentiation ability in male BMSCs and osteogenic ability in female BMSCs | E2 improves cellular senescence and proliferation in both sexes | [210] | |
In vitro; human articular chondrocytes | E2 treatment ranging from 10–11 to 10–7 M | Thymidine incorporation, ALP, RT-PCR for ER expression | E2-treated cells from female donors exhibited an increase in thymidine incorporation and ALP activity in a dose-dependent manner; no changes in thymidine incorporation or ALP activity seen in male cells with E2 treatment; no sex differences in ER expression when normalized to GAPDH | E2 stimulates proliferation and promotes osteogenic differentiation of female chondrocytes | [190] | |
In vitro; female menopausal versus non-menopausal monkey articular chondrocytes | Transfection with a reporter construct containing ER element/luciferase | RT-PCR, immunoblotting, IHC | Articular cartilage contained functional ERs from both menopausal and non-menopausal donors | E2 receptors are functional after menopause, indicating ERT is functional after menopause | [189] | |
In vivo; female monkey model | OVX female monkeys with and without ERT | Ligand blotting and immunoblotting to analyze production of IGFBPs; RT-PCR analysis for PG synthesis | IGFBP2 and PG expression was significantly increased in monkeys with ERT | ERT in menopausal females is chondroprotective | [189] |