The benefits of adipocyte metabolism in bone regeneration

Abstract

It is well known that patients suffering from disturbed fracture healing have to cope with diminished quality of life and ensue medical expenses for society. Such disorders represent the most expensive group of diagnoses in the emergency department and cause a significant health and economic impact worldwide. During bone regeneration, the interaction of immune cells and mesenchymal stromal cells by various paracrine or cell-cell driven mechanisms is indispensable to restore skeletal integrity. The osteogenic lineage formation is known to support bone regeneration, whereas the accumulation of the adipogenic lineage cells is widely thought to promote low grade inflammation and skeletal damage. Chronic low grade inflammation is largely caused by pro-inflammatory immune cells and inflamed adipose tissue, both of which are likely known causes of obesity and other metabolic disorders. This work hypothesizes, that a beneficial metabolic and immune-modulatory power of bone marrow adipocytes can be identified to support bone regeneration. Bone marrow adipocytes are highlighted as energy and metabolite providing partakers in conditions of high energetic demand such as bone healing. A regulatory effect of adipocyte secreted factors on the local inflammatory milieu is proposed. This pro-regenerative bone marrow adipose tissue is shown to be induced by the anti-inflammatory diabetes drug rosiglitazone activating the peroxisome proliferator-activated receptor γ (PPARG). To that end, PPARG agonist treatment, currently known as detrimental in relation to bone, was shown to induce bone marrow adipose tissue in the distal parts of the bone such as at the fracture site and at the distal growth plate. Surprisingly, the induction of adipocytes did not cause dysfunctional bone fracture healing but steered beneficial skeletal parameters during bone repair in osteotomized mice. Additionally, pro-osteogenic changes in the lipid compartment and the induction of anti-inflammatory CD4+ T helper 2 immune cells were identified. The specific features of PPARG agonist treated bone marrow adipocytes in regeneration were verified using human patient derived mesenchymal stromal cells isolated from bone. In accordance with the in vivo study, PPARG agonist treatment during osteogenic differentiation resulted in an increased osteogenic potential and mineralization as well as an enhanced metabolic fitness determined by higher OCR/ECAR ratios, higher oxidative spare capacity and an upregulation of glucose uptake. Interestingly, the secretion of adiponectin as specific paracrine effect of PPARG agonist treated adipocytes during osteogenic cultures could be determined as beneficial for bone formation. In this thesis, the possibility of using PPARG agonists, thiazolidinediones (TZDs), as short-term treatment to guide a pro-regenerative, metabolically active bone marrow adipose tissue further driving faster bone bridging was explored. PPARG driven effects were outlined as metabolic switch in MSCs during osteogenic differentiation and were shown to induce beneficial effects by secreting high amounts of anti-inflammatory adiponectin during mineralization. Hereby, the impact of PPARG agonist induced bone marrow adipose tissue on providing the necessary metabolites to sustain osteogenic stromal cells as well as polarizing an anti-inflammatory milieu during bone regeneration was highlighted.