Thyroid-stimulating hormone stimulation downregulates autophagy and promotes apoptosis in chondrocytes

Abstract

OSTEOARTHRITIS (OA) is the most common form of arthritis that affects about 3.8 % of people in the world [1]. OA results from the breakdown of articular cartilage, which is an avascular tissue with limited regenerative ability. As the only cell type in cartilage, the chondrocyte death / survival has a key role in cartilage maintenance and functionality. Apoptosis in chondrocytes has been detected in articular cartilage derived from OA patients [2], suggesting a crucial role for chondrocyte apoptosis in the pathogenesis of OA. However the mechanism is not fully understood. Abstract. Subclinical hypothyroidism (SCH) patients have normal thyroid hormone levels but increased thyroid stimulating hormone (TSH) level in serum. It has been reported that high TSH is related to abnormal skeletal development in mice with hypothyroidism. However, the cellular mechanism is not fully understood. In the present study, we aim to investigate the direct effects of TSH stimulation on chondrocytes, and the putative role of autophagy in this process. By using EdU incorporation assay and flow cytometry for mitochondrial membrane potential assay, we demonstrated deceased proliferation and promoted apoptosis in TSH stimulated primary mouse chondrocytes. And the balance of Bcl-2 and BAX expression on protein level was broken. More interestingly, the expression of autophagic markers Beclin-1 and LC3II was reduced in TSH stimulated chondrocytes, accompanied by less autophagosomes and accumulated p62 protein, indicating an impaired autophagic flux. More interestingly, mTOR was upregulated and AMPK activity was decreased in TSH stimulated PMCs, suggesting that mTOR/AMPK pathway is get involved in the regulation of TSH on autophagy in PMCs. Collectively, we found an increased apoptosis and suppressed autophagy in TSH stimulated primary chondrocytes, which is meaningful in understanding the effects of increased TSH level on articular cartilage and the role of autophagy in this process, and thus provide a potential novel therapeutic target in related cartilage damages.

TSH Combined with TSHR Aggravates Diabetic Peripheral Neuropathy by Promoting Oxidative Stress and Apoptosis in Schwann Cells

“…Specifically, based on cDNA array hybridization, Brokken et al revealed that most of the genes regulated by TSH are related to cell apoptosis [ 42 ]. Further, Xin et al reported that TSH stimulation upregulates Bax expression and downregulates Bcl2 expression, thus disrupts the balance between Bax and Bcl2, while promoting chondrocyte apoptosis [ 43 ]. It has also been reported that TSHR upregulation promotes the apoptosis of thyroid cancer cells [ 44 ].…”

Hormonal Regulation of Autophagy in Thyroid PCCL3 Cells and the Thyroids of Male Mice

“…Although p62 expression is reported to be up-regulated at the transcription levels in certain conditions [ 37-39 ], our results indicate that TSH decreases the degradation rate of p62, meaning that TSH action is at posttranslational rather than transcriptional levels. As mentioned in the Introduction, TSH is reported to suppress autophagy (as demonstrated by reduced LC3-II and increased p62 levels) in chondrocytes by inhibiting phosphorylation of AMPK [ 14 ]. The detailed mechanisms for the differences in our data and theirs are at present unknown, but TSH action on autophagy appears to be cellular context dependent.…”

“…However, regulation of autophagy in thyrocytes by hormones such as TSH and thyroid hormone (TH) has not been studied. We found 1 paper reporting TSH suppression of autophagy in chondrocytes [ 14 ], and several papers showing TH enhancement of autophagy in different types of mammalian cells, such as liver, muscle, and fat cells [ 15-17 ]. Hormonal regulation of autophagy has also been recently examined in various organs, such as Sertoli cells by testosterone, liver by growth hormone, and skeletal muscle by insulin (ref.…”

Can Panax Ginseng protect against fertility disorders in hypothyroid female albino rats?

“…(28) In consistence with the present result, Xin et al mentioned that TSH elevated with the hypothyroidism considered an apoptotic factor resulting in significant increase in serum 8-hydroxyguanosine and caspase-3. (29) The increasing in cortisol and stress oxidative markers in hypothyroid rats caused an elevation of reverse T 3 (rT3), which was interfered with beneficial activity of normal T 3 . Ginseng by its adaptogenic capability action could destroy the (rT3) and restore the cellular homeostasis.…”