Bone Growth and Repair

Poorer bone health particularly low bone mass is often seen in children and adolescents as a result of preterm birth, a low birth weight, chronic inactivity, poor nutrition or micronutrient deficiency, obesity, chronic illnesses and treatments. Our group aims to increase our cellular and molecular understanding of bone growth and devise novel micro-nutritional early interventions for enhancing bone growth and optimising bone mass accrual to improve both childhood and adult bone health. We study growth plate chondrocyte biology, osteoblast and osteocyte biology, and their regulation. We also investigate whether some bioactive natural substances can be used to modulate skeletal progenitor cells, bone growth, and bone mass accrual.

Trauma injury of children’s growth plate cartilage (which is responsible for bone growth) remains a key orthopaedic challenge as it is a common problem with 20% of fractures in children involving the growth plate and the injured growth plate is often repaired by faulty bony tissue leading to life-long bone growth defects. Our group aims to increase our understanding the underlying pathobiology and to develop progenitor cell/growth factor-based regenerative therapy. Using rodent models, we have identified sequential injury responses at the injury site (inflammatory, fibrogenic, osteogenic, remodelling), and defined critical roles of several signalling pathways involved in the growth plate faulty bony repair. These findings could provide potential intervention targets.

Bone fractures are common (due to accidents, osteoporosis, and/or weaker muscles). While most fractures can heal, about 10% cases (particularly complex fractures and critical size bone defects) cannot, which cause substantial morbidity and high healthcare expense/burden. While molecules (including bone morphogenic protein-2 which has been shown to be critical for bone healing) and pathways regulating fracture repair events are relatively well studied, repair of critical size bone defects remains a key orthopaedic challenge. Although BMP is used clinically or in clinical trials to promote bone healing, it is hugely costly and potentially risky due to the need of supraphysiological dosing. Our project aims to investigate how some growth factors and/or matrix proteins could modulate BMP activity in bone fracture healing, and positive outcomes can lead to novel approaches of optimising bone repair.

Glucocorticoid therapy in children is commonly, with up to 10% of children requiring some glucocorticoids mostly for treating inflammatory disorders. Glucocorticoids are also used frequently in childhood chemotherapy; and together with other cytotoxic anti-cancer drugs, which can cure >75% of children with the major childhood cancer (acute lymphoblastic leukaemia or related blood cancers). While these medical therapies have become more successful, they cause significant bone growth impairments. We have been investigating the underlying mechanisms for the associated bone growth defects and the bone/bone marrow regeneration potential. We have identified that these defects result from the damaging effects on bone growth and remodelling mechanisms, by reducing bone formation, increasing bone resorption, and increasing marrow fat content, involving major signalling pathways. We also aim to develop supplementary preventative treatments.

Bone loss, excess bone marrow fat, fractures, and bone pain have become more prevalent in cancer patients and survivors, due to the greater success of chemotherapy regimens and the improved survivorship. Our group aims to establish the mechanisms for, and prevention of, these chemotherapy chronic skeletal side effects. Using rodent models, we found cancer chemotherapy causes (1) aggravated osteoclast formation and bone resorption due to induction of pro-inflammatory cytokine/NF-kB signalling; and (2) reduced bone formation but increased fat formation in the bone marrow due to the attenuation of Wnt/b-catenin signalling. We have also observed that supplementation with folinic acid prevented bone defects caused by the commonly used cancer drug anti-metabolite methotrexate (MTX), and that genistein (a soy isoflavone) and anti-inflammatory oils inhibited osteoclast formation and preserved bone mass during chemo in rats.