High Levels of Tumor Necrosis Factor-α Contribute to Accelerated Loss of Cartilage in Diabetic Fracture Healing

Abstract

Diabetes interferes with fracture repair; therefore, we investigated mechanisms of impaired fracture healing in a model of multiple low-dose streptozotocin-induced diabetes. Microarray and gene set enrichment analysis revealed an up-regulation of gene sets related to inflammation, including tumor necrosis factor (TNF) signaling in the diabetic group, when cartilage is being replaced by bone on day 16, but not on days 12 or 22. This change coincided with elevated osteoclast numbers and accelerated removal of cartilage in the diabetic group (P < 0.05), which was reflected by smaller callus size. When diabetic mice were treated with the TNF-specific inhibitor, pegsunercept, the number of osteoclasts, cartilage loss, and number of TNF-␣ and receptor activator for nuclear factor kB ligand positive chondrocytes were significantly reduced (P < 0.05). The transcription factor forkhead box 01 (FOXO1) was tested for mediating TNF stimulation of osteoclastogenic and inflammatory factors in bone morphogenetic protein 2 pretreated ATDC5 and C3H10T1/2 chondrogenic cells. Osteopenia associated with decreased bone mineral density is an important complication of type 1diabetes.

Determining the Role of Sost and Sostdc1 During Fracture Healing

“…This indicates that different diabetic rodent models may serve as a representative of a subpopulation of T1DM patients for evaluating drug treatment studies. Altered osteoclast activity can be detrimental for bone repair since increased osteoclast activity may remove cartilage prematurely resulting in smaller callus size and impaired cartilage to bone transition [20,49]. In contrasts, decreased osteoclast activity can also impair fracture repair since osteoclasts is valuable for removing damaged bone.…”

“…Previous studies observed an up-regulation of the levels of pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha), and the osteoclast activity on chondrocytes during inflammation stage of fracture repair in diabetic mice [20]. The combination of elevated inflammation response and enhanced osteoclast activity may result in delayed chondrogenesis and maturation, angiogenesis, and elevated cartilage resorption [21] [19].…”

The role of the microenvironment on the fate of adult stem cells

“…They also have elevated levels of serum sclerostin and reduced levels of serum β-catenin. In animal experiments, streptozotocin has been used to break insulin-producing beta cells in the pancreas and thus produces a disease that mimics type I diabetes [54,55]. In a rat model of streptozotocin-induced diabetes, the proliferation of chondroprogenitor cells is similarly reduced at post-fracture days 4 and 7, with decreased cartilage formation and delayed union [56,57].…”

Interactions Between Multipotential Stromal Cells (MSCs) and Immune Cells During Bone Healing

“…Additionally, TNF-induces the production of M-CSF by BM MSCs, which in turn, enhance the expression of the key osteoclastogenic cytokine receptor, RANK in the osteoclast progenitors (190). Targeting TNF-in these models reversed these effects and improved bone healing (187).…”

“…TNF-mediated chronic inflammation in a diabetic mouse model has been shown to lead to the death of regenerating chondrocytes thus impairing the bone formation (186,187).…”