Growth hormone regulating chondrocyte metabolism for osteoarthritis development

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Project Summary Most older adults (~60 years of age) have some signs of osteoarthritis (OA) in their joints. Unfortunately, there are no disease-modifying therapies for OA due to our lack of insight into the underlying pathophysiology. GH is an FDA approved drug to treat certain diseases such as growth hormone deficiency (GHD). Additionally, GH secretion decreases over time, causing some older adults to consider the use of GH replacement as a means to counteract aging related conditions. However, over-production or prolonged usage of GH has been reported to have many side effects including joint degeneration and joint pain. Identifying the mechanisms by which GH causes joint cell dysfunction during aging could inform effective interventions and therapeutic strategies that reduce the incidence and impact of OA. Our preliminary studies have shown that over-expression of GH gene in mice predispose mice into progressive joint degeneration, while blocking GH action through systemic GH receptor disruption protect mice from developing OA. We showed that GH robustly altered the metabolism of cells (i.e, chondrocytes) in cartilage. Yet, it is still unknown if blocking GH’s action specifically on cartilage tissue would be protective. Guided by our preliminary data and the literature, we will investigate this question via three specific aims: Aim 1. Determine how blocking GH action on cartilage through cartilage specific deletion of GHR affects OA development; Aim 2. Determine the mechanisms by which GH promotes chondrocyte hypertrophic changes and OA development. Aim 3. Determine if GH receptor antagonism (GHa) protects mice from developing OA. Well-established mouse models GH over-expression and GH receptor tissue specific deletion will be used to examine the consequences of enhancing or inhibiting GH action in cartilage on OA pathology. In vivo and in vitro metabolic profiling methods will be leveraged to determine the effects of manipulating GH signaling on chondrocyte cellular metabolism. Last but not least, a unique mouse model that was used for discovery of Pegvisomant, an FDA approved drug for treating acromegaly, will be used to test if blocking GH is beneficial for joint health. Successful completion of this research is expected to provide more comprehensive understanding of how GH affects joint cell functions, offering the potential to provide new therapeutic targets for OA treatment.