Excessive growth hormone promotes joint degeneration and chondrocyte metabolic dysfunction in mice

Abstract

Many patients with acromegaly, a hormonal disorder with excessive growth hormone (GH), report pain in joints. The objective of this study is to characterize the joint pathology of mice with over-expression of either bovine GH (bGH) or a GH receptor antagonist (GHa). We also investigate the effect of GH on regulation of chondrocyte cellular metabolism. Knee joints from mice over-expressing bGH or GHa and WT were histologically and μCT analyzed for OA pathologies. Additionally, cartilage from bGH mice was used for metabolomics. Mouse primary chondrocytes from WT or bGH mice with or without Pegvisomant (Peg) treatment were used for Q-PCR and Seahorse Respirometry analysis. Both male and female bGH mice at ~13 months had increased knee joint degeneration, which is characterized by loss of cartilage structure, expansion of hypertrophic chondrocytes, synovitis, and subchondral plate thinning. The joint pathologies were also demonstrated by significantly higher OARSI and Mankin scores in bGH compared with WT mice. Metabolomics revealed changes of a wide range of metabolic pathways in bGH mice including beta-alanine metabolism, tryptophan metabolism, lysine degradation, and ascorbate and aldarate metabolism. Also, bGH chondrocytes upregulated fatty acid oxidation (FAO) and increased expression of Col10a. Joints of GHa mice are remarkably protected from developing age-associated joint degeneration with smooth articular joint surface. These studies uncover that an excessive amount of GH promotes joint degeneration in mice, whereas antagonizing GH action through a GHa protects mice from OA development, which is associated with chondrocyte metabolic dysfunction and hypertrophic changes.