The role of tumour necrosis factor alpha stimulated gene-6 on bone

Thesis

Osteoporosis, a metabolic disorder of the skeletal system, currently affects 200 million people worldwide. Osteoporosis is caused by an imbalance in bone resorption and formation due to either molecular mutations, oestrogen reduction at menopause, oxida-tive stress, as well as life style, leading to a characteristic low bone density and/or thin-ning that predisposes patients to skeletal fracture and breakage upon minimal physical trauma. Depending on the severity of the disease, most patients are often treated with calcium/vitamin D and anti-resorptive drugs such as bisphosphonates or calcitonin. However, there are few options for bone formation using anabolic agents- such as Teriparatide (PTH_1-34), which have limited success, creating an unmet need for novel anabolic interventions.

The rapidly-advancing field of osteoimmunology recognises the close and finely-tuned interaction between the immune system and musculoskeletal organisation. In an at-tempt to identify immune-derived cells and soluble factors that induce the differentiation of stem cells towards the osteoblast lineage, the interaction between monocytes and osteoblast precursors has proven a potentially promising approach.

One of the factors identified from this screening was TSG-6 – a secreted protein with immunomodulatory and chondroprotective properties.

This study aimed to generate adequate amounts of biologically active TSG-6 protein to test its role on bone formation in vivo during physiology and disease - using oestrogen-deficiency induced bone loss in mice as a model of osteoporosis. TSG-6 was not found to protect bone tissue against the effects of oestrogen-deficiency induced bone loss, as determined by global TSG-6 knockout and systemic exogenous administration studies. However, local delivery of full-length TSG-6 significantly enhanced mineral apposition rate in a dose-dependent manner, and in vitro studies found TSG-6 significantly enhanced alkaline phosphatase levels of primary bone marrow-derived human mesenchymal stem cells in vitro, in the presence of BMP-2.

Contrary to its previously reported inhibitory effects on osteoblastogenesis, this thesis shows, for the first time, that TSG-6 displays context-specific anabolic properties. This finding implies a therapeutic value for the protein, with possibilities of being used in conjunction with BMP-2 to treat local bone injuries such as fractures.

Authors: Afrough, S

• DOI: 10.5287/ora-pvj5jj0ax
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford