Effects of insulin-like growth factor-1 and dexamethasone on cytokine-challenged cartilage: relevance to post-traumatic osteoarthritis

SummaryObjectiveInterleukin-1 is one of the inflammatory cytokines elevated after traumatic joint injury that plays a critical role in mediating cartilage tissue degradation, suppressing matrix biosynthesis, and inducing chondrocyte apoptosis, events associated with progression to post-traumatic osteoarthritis (PTOA). We studied the combined use of insulin-like growth factor-1 (IGF-1) and dexamethasone (Dex) to block these multiple degradative effects of cytokine challenge to articular cartilage.MethodsYoung bovine and adult human articular cartilage explants were treated with IL-1α in the presence or absence of IGF-1, Dex, or their combination. Loss of sulfated glycosaminoglycans (sGAG) and collagen were evaluated by the DMMB and hydroxyproline assays, respectively. Matrix biosynthesis was measured via radiolabel incorporation, chondrocyte gene expression by qRT-PCR, and cell viability by fluorescence staining.ResultsIn young bovine cartilage, the combination of IGF-1 and Dex significantly inhibited the loss of sGAG and collagen, rescued the suppression of matrix biosynthesis, and inhibited the loss of chondrocyte viability caused by IL-1α treatment. In adult human cartilage, only IGF-1 rescued matrix biosynthesis and only Dex inhibited sGAG loss and improved cell viability. Thus, the combination of IGF-1 + Dex together showed combined beneficial effects in human cartilage.ConclusionsOur findings suggest that the combination of IGF-1 and Dex has greater beneficial effects than either molecule alone in preventing cytokine-mediated cartilage degradation in adult human and young bovine cartilage. Our results support the use of such a combined approach as a potential treatment relevant to early cartilage degradative changes associated with joint injury

The triterpene echinocystic acid and its 3-O-glucoside derivative are revealed as potent and selective glucocorticoid receptor agonists

Glucocorticoids are steroid hormones widely used to control many inflammatory conditions. These effects are primarily attributed to glucocorticoid receptor transrepressional activities but with concomitant receptor transactivation associated with considerable side effects. Accordingly, there is an immediate need for selective glucocorticoid receptor agonists able to dissociate transactivation from transrepression. Triterpenoids have structural similarities with glucocorticoids and exhibit anti-inflammatory and apoptotic activities via mechanisms that are not well-defined. In this study, we examined whether echinocystic acid and its 3-O-glucoside derivative act, at least in part, through the regulation of glucocorticoid receptor and whether they can constitute selective receptor activators. We showed that echinocystic acid and its glucoside induced glucocorticoid receptor nuclear translocation by 75% and 55%. They suppressed the nuclear factor-kappa beta transcriptional activity by 20% and 70%, respectively, whereas they have no glucocorticoid receptor transactivation capability and stimulatory effect on the expression of the phosphoenolopyruvate carboxykinase target gene in HeLa cells. Interestingly, their suppressive effect is diminished in glucocorticoid receptor low level COS-7 cells, verifying the receptor involvement in this process. Induced fit docking calculations predicted favorable binding in the ligand binding domain and structural characteristics which can be considered consistent with the experimental observations. Further, glucocorticoids exert apoptotic activities; we have demonstrated here that the echinocystic acids in combination with the synthetic glucocorticoid, dexamethasone, induce apoptosis. Taken together, our results indicate that echinocystic acids are potent glucocorticoid receptor regulators with selective transrepressional activities (dissociated from transactivation), highlighting the potential of echinocystic acid derivatives as more promising treatments for inflammatory conditions

Tissue-Specific Actions of Glucocorticoids on Apoptosis: A Double-Edged Sword

First described for their metabolic and immunosuppressive effects, glucocorticoids are widely prescribed in clinical settings of inflammation. However, glucocorticoids are also potent inducers of apoptosis in many cell types and tissues. This review will focus on the established mechanisms of glucocorticoid-induced apoptosis and outline what is known about the apoptotic response in cells and tissues of the body after exposure to glucocorticoids. Glucocorticoid-induced apoptosis affects the skeletal system, muscular system, circulatory system, nervous system, endocrine system, reproductive system, and the immune system. Interestingly, several cell types have an anti-apoptotic response to glucocorticoids that is cytoprotective. Lastly, we will discuss the pro- and anti-apoptotic effects of glucocorticoids in cancers and their clinical implications

Tissue-Specific Actions of Glucocorticoids on Apoptosis: A Double-Edged Sword

First described for their metabolic and immunosuppressive effects, glucocorticoids are widely prescribed in clinical settings of inflammation. However, glucocorticoids are also potent inducers of apoptosis in many cell types and tissues. This review will focus on the established mechanisms of glucocorticoid-induced apoptosis and outline what is known about the apoptotic response in cells and tissues of the body after exposure to glucocorticoids. Glucocorticoid-induced apoptosis affects the skeletal system, muscular system, circulatory system, nervous system, endocrine system, reproductive system, and the immune system. Interestingly, several cell types have an anti-apoptotic response to glucocorticoids that is cytoprotective. Lastly, we will discuss the pro- and anti-apoptotic effects of glucocorticoids in cancers and their clinical implications