2. Academic Validation
  3. FSH modulated cartilage ECM metabolism by targeting the PKA/CREB/SOX9 pathway

FSH modulated cartilage ECM metabolism by targeting the PKA/CREB/SOX9 pathway

  • J Bone Miner Metab. 2021 Sep;39(5):769-779. doi: 10.1007/s00774-021-01232-3.
Mengqi Zhang 1 2 3 4,  Yan Wang 1 2 3 4,  Zhikun Huan 1 2 3 4,  Yaping Liu 1 2 3 4 5,  Wenwen Zhang 1 2 3 4 6,  Dehuan Kong 7,  Lei Kong  # 8 9 10 11,  Jin Xu  # 12 13 14 15
Affiliations

Affiliations

  • 1 School of Medicine, Shandong University, jinan, 250021, shandong, China.
  • 2 Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jina, 250021, Shandong, China.
  • 3 Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 4 Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China.
  • 5 Department of Endocrinology, Jining No.1 People's Hospital, No.6 Health Road, Jining, 272011, China.
  • 6 Scientific Center, Shandong Provincial Hospital Affiliated To Shandong University, Jinan, Shandong, China.
  • 7 Department of Geriatrics, Taian City Central Hospital, Taian, Shandong, China.
  • 8 School of Medicine, Shandong University, jinan, 250021, shandong, China. lgkonglei@hotmail.com.
  • 9 Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jina, 250021, Shandong, China. lgkonglei@hotmail.com.
  • 10 Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. lgkonglei@hotmail.com.
  • 11 Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China. lgkonglei@hotmail.com.
  • 12 School of Medicine, Shandong University, jinan, 250021, shandong, China. xujin267903@163.com.
  • 13 Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jina, 250021, Shandong, China. xujin267903@163.com.
  • 14 Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. xujin267903@163.com.
  • 15 Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China. xujin267903@163.com.
  • # Contributed equally.
PMID: 33988757 DOI: 10.1007/s00774-021-01232-3
Abstract

Introduction: Osteoarthritis (OA) is a common joint disease characterized by articular cartilage degeneration. The prevalence of OA is higher among women than men, and this prevalence is closely related to menopause. The classic view assumes that the underlying mechanism of postmenopausal OA is attributed to declining estrogen levels. Although follicle-stimulating hormone (FSH) levels become elevated in parallel, the effects of FSH on OA have been poorly explored. The present study aimed to study the effect of FSH on cartilage metabolism.

Methods: Chondrocyte-like ATDC5 cells were treated with recombinant FSH protein. Then the cell viability was measured using cell counting kit-8 assay. Expressions of crucial factors involved in the extracellular matrix (ECM) metabolic and PKA-CREB-SOX9 pathway were analyzed by western blot, RT-qPCR, and immunofluorescence staining. Intracellular cAMP levels were assessed by ELISA assay. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM) surgery. Adeno-associated virus expressing shRNA against FSHR (AAV-shFSHR) was intra-articular (IA) injected into the OA model Animals to specifically knock down FHSR in cartilage. Histological staining and OARSI scores were used to assess the efficacy of AAV-shFSHR injections.

Results: We found that FSH down-regulated the expression of ECM-related proteins in chondrocyte-like ATDC5 cells. The underlying mechanism is probably associated with regulating PKA/CREB/SOX9 pathway. Besides, blocking FSH signaling via shRNA-mediated downregulation of FSHR in joint tissues effectively delayed the development of posttraumatic OA in mice.

Conclusions: Our results collectively indicated that FSH plays an essential role in the pathogenesis of OA and acts as a crucial mediator.

Keywords

Extracellular matrix; Follicle-stimulating hormone; Osteoarthritis; PKA.

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