FSH directly regulates chondrocyte dedifferentiation and cartilage development

Abstract

Previous studies suggest that postmenopausal osteoarthritis is linked to a decrease in estrogen levels. However, whether follicle-stimulating hormone (FSH), the upstream hormone of estrogen, affects cartilage destruction and thus contributes to the onset of osteoarthritis has never been explored. To evaluate the potential involvement of FSH in joint degeneration and to identify the molecular mechanisms through which FSH influences chondrocytes, mouse cartilage chondrocytes and the ATDC5 chondrocyte cell line were treated with FSH and inhibitors of intracellular signaling pathways. We observed that FSH induces chondrocyte dedifferentiation by decreasing type II collagen (Coll-II) synthesis. Chondrocyte cytoskeleton reorganization was also observed after FSH treatment. The FSH-induced decrease in Coll-II was rescued by ERK-1/2 inhibition but aggravated by p38 inhibition. In addition, knocking down the FSH receptor (Fshr) by using Fshr siRNA abolished chondrocyte dedifferentiation, as indicated by the increased expression of Coll-II. Inhibition of the protein Gαi by pertussis toxin (PTX) also restored FSH-inhibited Coll-II, suggesting that Gαi is downstream of FSHR in chondrocyte dedifferentiation. FSHβ antibody blockade prevented cartilage destruction and cell loss in mice. Moreover, decreased Coll-II staining due to the progression of aging could be rescued by blocking FSH. Thus, we suggest that high circulating FSH, independent of estrogen, is an important regulator in chondrocyte dedifferentiation and cartilage destruction.

Males and Females Have Distinct Molecular Events in the Articular Cartilage during Knee Osteoarthritis

“…Although estrogen is considered to have protective potency against OA, the effects of estrogen replacement therapy and selective estrogen receptor modulators in preserving and/or restoring joint tissue in OA are controversial among currently published reports [13,14]. Besides estrogen, sex hormone-binding globulin [15], follicle-stimulating hormone [16], dehydroepiandrosterone [17], progesterone [18], and testosterone [19] may all influence OA progression. However, none of these sex hormones can completely explain all differences observed between male and female OA patients [20].…”

A network medicine approach to elucidate mechanisms underlying menopause-induced knee osteoarthritis

“…These effects were quantified by effect size, betweenness (i.e., capacity of a protein to communicate with distant proteins( 59 )), and centroid (i.e., probability of a protein to be functionally capable of organizing downstream proteins( 59 )) ( Figure S4C-E ). Although many studies have implied that loss of estradiol( 42, 60–62 ) and heightened FSH levels( 63–65 ) may drive KOA, these findings implicate a previously unrecognized role of disrupted progesterone, relaxin, and LH signaling in mediating cartilage homeostasis.…”

EGF‐driven EGFR/miR‐27b‐3p/FOXO1 promotes rat FSH synthesis and secretion

“…It has also been linked to reproductive disorders such as polycystic ovary syndrome 4 and infertility 5 . Moreover, outside the reproductive system, FSH plays important roles in biological activities and is an important target for treating diseases 6,7 . FSH is widely utilized in animal reproduction regulation and other areas.…”

“…and is an important target for treating diseases. 6,7 FSH is widely utilized in animal reproduction regulation and other areas. Research has shown that FSH plays a crucial role in the growth, development, and reproduction of organisms.…”