Prevention of growth failure caused by glucocorticoids and inflammation

Longitudinal bone growth is a complex process that takes place in the growth plate, and normal growth is dependent on a precise balance of several endocrine and paracrine factors. Growth impairment is common in children with inflammatory diseases and is associated with elevated levels of pro-inflammatory cytokines and long-term glucocorticoid treatment. To date, no treatments are available to treat growth impairment caused by glucocorticoids and there is a need to find new strategies to counteract the negative side effects of glucocorticoids on bone growth.

The aim of this thesis was to study bone growth impairment induced by glucocorticoids and inflammation and the underlying molecular mechanisms. The aim was also to address whether the mitochondrial derived peptide humanin potentially could rescue from glucocorticoid-induced bone growth impairment and apoptosis in the growth plate, without interfering with the anti-inflammatory effect of glucocorticoids.

In study I the effect of glucocorticoids and humanin on bone growth was assessed in several different experimental models. We discovered that the synthetic humanin analogue, HNG, completely rescued from dexamethasone-induced bone growth impairment and that humanin over-expressing mice were resistant to glucocorticoid-induced growth impairment. In addition, our results indicate that humanin is a novel regulator of Hedgehog signaling. In study II we assessed whether HNG could rescue from glucocorticoid-induced apoptosis in the growth plate in a model of chronic inflammation. We showed that HNG treatment suppressed apoptosis in both growth plate and articular cartilage. Importantly, we found that HNG did not interfere with the anti-inflammatory effect of dexamethasone. In study III we investigated the effect of dexamethasone on bone growth and chondrogenesis in a disease model of chronic inflammation. By using the transgenic TNF over-expressing mouse model (tgTNF) we found that chronic inflammation by itself suppressed bone growth and that dexamethasone treatment further suppressed bone growth despite its anti-inflammatory actions. We also showed that Indian hedgehog and humanin expression levels were suppressed in the growth plate of the tgTNF mice, suggesting a new mechanism for inflammation induced growth impairment.

List of scientific papers

I. Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid-induced bone growth impairment. Farasat Zaman, Yunhan Zhao, Bettina Celvin, Hemal Mehta, Junxiang Wan, Dionisios Chrysis, Claes Ohlsson, Bengt Fadeel, Pinchas Cohen and Lars Sävendahl. FASEB J. (2019) 33(4): 4962-74.
https://doi.org/10.1096/fj.201801741R

II. Humanin prevents undesired apoptosis of chondrocytes without interfering with the anti-inflammatory effect of dexamethasone in collagen-induced arthritis. Bettina Celvin, Farasat Zaman, Cecilia Aulin and Lars Sävendahl. Clin Exp Rheum. (2019) 38(1): 129-135.
https://pubmed.ncbi.nlm.nih.gov/31172921

III. Dexamethasone suppresses bone growth and chondrogenesis in TNF-overexpressing mice. Bettina Celvin, Yunhan Zhao, Maria Denis, Niki Karagianni, Cecilia Aulin, Farasat Zaman and Lars Sävendahl. [Manuscript]