Abstract
The mechanistic basis of obesity-associated intervertebral disc degeneration (IDD) is unclear. Aberrant expression of aggrecan and its degrading enzymes ADAMTS-4 and ADAMTS-5 is implicated in the development of IDD. Here, we investigated the effect of leptin, a hormone with increased circulating levels in obesity, on the expression of aggrecan and ADAMTSs in primary human nucleus pulposus (NP) cells. Real-time PCR and Western blots showed that leptin increased the mRNA and protein expression of ADAMTS-4 and ADAMTS-5 and reduced the level of aggrecan in NP cells, accompanied by a prominent induction of p38 phosphorylation. Treatment of NP cells with SB203580 (a p38 inhibitor) abolished the regulation of aggrecan and ADAMTSs by leptin. Knockdown of ADAMTS-4 and ADAMTS-5 by siRNAs also attenuated the degradation of aggrecan in leptin-stimulated NP cells. To conclude, we demonstrated that leptin induces p38 to upregulate ADAMTSs and thereby promoting aggrecan degradation in human NP cells. These results provide a novel mechanistic insight into the molecular pathogenesis of obesity-associated IDD.
Highlights
Musculoskeletal disorders of the spine are leading causes of disability in people younger than 45 years old and result in national economic losses of more than 90 billion dollars per year in China [1]
We demonstrated that leptin induces p38 to upregulate ADAMTSs and thereby promoting aggrecan degradation in human nucleus pulposus (NP) cells
Results showed that leptin could time-dependently increased ADAMTS-4 and ADAMTS-5 protein expression (Fig. 2B)
Summary
Musculoskeletal disorders of the spine are leading causes of disability in people younger than 45 years old and result in national economic losses of more than 90 billion dollars per year in China [1]. Disc degeneration of the spine is considered to be one of the underlying factors of low back pain [2]. Intervertebral disc degeneration (IDD) is a multi-factorial process that is influenced by lifestyles, genetic predisposition, co-morbidities, and aging [3]. The balance is shifted towards degradation in IDD, with alterations in collagen type and a decrease in proteoglycan content, leading to the loss of tissue integrity [6]. To this end, the loss of aggrecan, a major type of proteoglycan, is considered to be an early biochemical abnormality of IDD [7]
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