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

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.

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Acknowledgments

This research was supported by the Key Research and Development Plan Project of Shandong Province (Grants no. 2016 GSF201025, 2016GGH3118), the National Natural Science Foundation of China (Grant no. 81370892), and the Shandong Taishan Scholars Specially invited Expert Plan.

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Contributions

MZ, YW, JX, and LK: designed the experiments. MZ and YW: conducted in vivo experiments; MZ, YW, ZH: conducted the cell experiments. WZ, YL, and DK: analyzed the results, MZ: wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Lei Kong or Jin Xu.

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Zhang, M., Wang, Y., Huan, Z. et al. FSH modulated cartilage ECM metabolism by targeting the PKA/CREB/SOX9 pathway. J Bone Miner Metab 39, 769–779 (2021). https://doi.org/10.1007/s00774-021-01232-3

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Keywords

  • Osteoarthritis
  • Follicle-stimulating hormone
  • Extracellular matrix
  • PKA