Experimental growth research – Lars Sävendahl's research group

Research projects

Modulation of Growth Plate Cartilage by SERMs; A Novel Strategy to Prevent Extreme Tall Stature

Excessive growth and extreme tall stature often cause problems, especially during the adolescent period. It is now almost 40 years since treatment with high-dose oestrogen was described to reduce final height in the adolescent tall female. Today, we know that oestrogen receptors (ERalpha,ERbeta) are expressed in the human growth plate, and that a lack of oestrogen receptor alpha prevents growth plate fusion in humans. Thus, it is undisputable that estrogens play a crucial role in the process of promoting growth plate fusion.

Today, we have also learned that high-dose oestrogen therapy appears to increase the risk of deep vein thrombosis and may increase the risk of breast and gynaecological cancers and reduce fertility later in life. Alternative medical treatment to prevent extreme tall stature is therefore needed. Selective Estrogen Receptor Modulators (SERMs) display selective tissue-specific agonistic and antagonistic effects due to different binding affinity to ERalpha and/or ERbeta.

I hypothesize that selective oestrogen receptor modulators (SERMs), have the potential to be used as alternative treatment to modulate growth in growth disorders minimizing the potential side-effects. To test my hypothesis I employ different models i.e. human chondrocytes, organ culture of fetal and postnatal rat metatarsal bones and animal models.

Previously, we have shown that Raloxifene, a SERM, promote growth plate fusion in the ovariectomized rabbit. Recently, I have shown that Tamoxifen, the first SERM became available, induces growth retardation in intact young male rats. The gathered results within this project could open the door to new strategies using SERMs to prevent extreme tall stature in adolescents, thereby minimizing the known side effects associated with todays treatment with high-dose sex steroids.

Elham Karimian, MD, PhD

Bone development and cancer - Novel anti-cancer drugs: the mechanism(s) of action and devising strategies to avoid side effects in cancer patients

In the cancer cells, the drugs act by interfering with the duplication and growth of the cell, primarily inhibiting proliferation and or inducing apoptosis. While chemotherapy helps to treat cancer, it can also target normal cells in the body called side effects. Because of this, unwanted side effects of chemotherapy often appear either during or after treatment.

Bone is often seen for common side effect of chemotherapy in children. Longitudinal bone growth takes place in the growth plate and studies have shown that altered apoptosis in the growth plate leads to aberrant longitudinal growth.

Presently, I am working on following projects:

- Proteasome inhibitors (PIs) are new exciting drugs which can induce cancer cell-apoptosis and are under clinical trials for their wider application in cancer therapy. While investigating the unknown effects of PIs on bone, I found that dysfunction of ubiquitin/proteasome system (in vivo) affects bone in a tissue specific manner and causes growth retardation. This effect on growth was due to massive apoptosis (p53 and AIF mediated) of chondrocytes. Collaborating with Bengt Fadeel (Associate Professor of Toxicology), I am also investigating programmed cell clearance (PCC) within growth plate.

- Dexamethasone (a widely used Glucocorticoid) is widely used in the treatment of different diseases especially in childhood cancers. As a result, short stature and osteoporosis are important long-term side effects in cancer survivors. Our previous results show that growth retardation induced by dexamethasone is at least partially due to increased apoptosis in the growth plate. Recently, we have reported that dexamethasone induced apoptosis in proliferative chondrocytes is mediated through caspases and suppression of the PI3K-signalling pathway. I am further investigating the mitochondrial mediated apoptosis in chondrocytes, and also that if it can be reversed by using small anti-apoptotic peptides or suppression of genes (siRNA).

Farasat Zaman, BS (Hons), PhD

Underlying mechanisms and prevention of growth retardation

Dionysios Chrysis, MD, PhD

Imaging techniques of the human growth plate

Evaldas Laurencikas, MD, PhD

Tall stature; associated problems and treatment

In Sweden, a common definition of tall stature has been an adult height exceeding 200 cm in boys and 185 cm in girls.

Tall stature is most often caused by genetic factors. Nutrition, endocrine function and socioeconomic status can also influence growth. In some cases an underlying disorder is present.

The general aim of the research is to identify medical and/or social problems related to extreme tall stature and its current treatment thereby facilitating the tailoring of new effective and safe alternative treatment modalities that will be investigated within this PhD project.

Emelie Bunyi, MD, PhD

PhD projects

Estrogen actions in growth plate cartilage

The overall scientific objective of this PhD project is to identify new drug targets allowing the specific modulation of longitudinal bone growthNew treatment of growth failure and osteoporosis caused by glucocorticoids and inflammation.

Maryam Iravani, PhD student

New treatment of growth failure and osteoporosis caused by glucocorticoids and inflammation

The overall scientific objective is to identify new drug targets allowing the prevention of short stature and osteoporosis caused by chronic inflammatory disorders and/or secondary to the treatment with glucocorticoids.

Bettina Sederquist, PhD student

GH action in the growth plate

Growth Hormone (GH) is widely used to treat short stature caused by GH-deficiency. It is routinely given as daily subcutaneous injections. It is believed that GH acts both locally and systemically.

In the growth plate GH increases local production of Insulin-like Growth Factor-I (IGF-I) and stimulates the recruitment of chondrocytes from the resting zone into the proliferative layer. Moreover, GH stimulates production of liver-derived IGF-I, which in turn promotes chondrocyte proliferation and differentiation.

Despite widely used, the mechanism of GH action in the growth plate as well its interaction with IGF-I is not completely clear. Recently we have established an experimental model for long-term cultures of postnatal rat metatarsal bones. In our experimental conditions metatarsal bones from young rats grow for several months. This model is currently the best in vitro model of linear growth and reflects the human situation with regards to hormonal regulation of longitudinal growth.

To investigate different possible treatment regimes of GH and IGF-I employing our newly developed model of cultures of postnatal rat metatarsal bones. Postnatal rat metatarsal bones will be cultured in vitro in the presence of different concentrations of IGF-I and GH. Bone growth will be measured and levels of chondrocyte differentiation and proliferation will be analyzed. New possible treatment regimes could become beneficial by improving the outcome of the GH and/or IGF-I treatment in regards of longitudinal growth, by reducing the cost of the treatment and by reducing the inconvenience for the children.Short- and long-term safety of childhood growth hormone treatment

Katja Sundström, PhD student

Short- and long-term safety of childhood growth hormone treatment

The overall objective of this PhD project is to investigate the short- and long-term safety of childhood growth hormone treatment.

Anders Tidblad, PhD student

Contact: Lars Sävendahl, Professor, group leader