TGF‐beta pathway inhibition as the therapeutic acceleration of diabetic bone regeneration

Abstract

Bone regeneration and fracture healing are impaired in diabetic patients due to defective functions of associated cells. Thus, the search for molecular causes and new treatment strategies are of particular clinical relevance. We investigated the gene expression profile of bones from type 2 diabetic (db−/db−) mice and wild‐type (wt) mice by comparative microarray analyses before and after placing tibial defects and examined the expression of several osteogenesis‐ and osteoclastogenesis‐related markers by quantitative real‐time polymerase chain reaction. In regenerating wt bones, pathways related to, for example, inhibition of matrix metalloproteases were activated, whereas in db−/db− bones activation of pathways related to, for example, osteoarthritis, transforming growth factor‐beta (Tgfb), or hypoxia‐inducible factor 1a were detected during regeneration. We defined the Tgfb pathway as a potential therapeutic target and locally applied a single dose (0.5 µg) of the Tgfb 1, 2, and 3 neutralizing antibody 1D11 on tibial defects in db−/db− mice (n = 7). Seven days postoperation, histological and immunohistochemical stainings were performed. Decreased bone regeneration, osteogenic differentiation, osteoclast invasion, and angiogenesis in db−/db− mice were significantly restored by local 1D11 application in comparison to the phosphate‐buffered saline controls. Thus, local treatment of db−/db− bony defects with Tgfb neutralizing antibody 1D11 might be considered a good candidate for the successful acceleration of bone regeneration.

Reversal of the diabetic bone signature with anabolic therapies in mice

“…Four of the genes upregulated in diabetic bone have been previously associated with glucose homeostasis, lipid metabolism, or pancreatic β cell function (Table 1). [11][12][13] Among the genes downregulated by T2-DM, Stearoyl-coenzyme A desaturase-1 (Scd1) was the most significantly downregulated (−2.9 fold), and it was conversely significantly upregulated only by ABL ( + 1.4 fold) (Fig. 4a and Table 1).…”

Contribution of Extracellular Particles Isolated from Morus sp. (Mulberry) Fruit to Their Reported Protective Health Benefits: An In Vitro Study

“…Furthermore, in that study, TGF-β induced an invasive (pro-migratory) response in 2d culture, which was inhibited via the addition of bFGF [ 31 ]. In an in vivo model of diabetic bone degeneration, the blockade of TGFβ using a neutralizing antibody led to a significant improvement in bone regeneration [ 32 ]. It is important to note that whilst the Alamar Blue proliferation assay ( Figure 5 ) demonstrated a net increase in cell proliferation, we did not specifically measure apoptosis or necrosis.…”

TGF-β signaling in health, disease and therapeutics

“…Adverse events that occurred during the study regardless of attribution mainly included pruritus, fatigue, abdominal pain, anemia, and thrombocytopenia. 958 Additionally, other potential applications of neutralizing TGF-β antibodies suggested by pre-clinical studies include wound healing, 334,959,960 prostatic hyperplasia, 961 pulmonary diseases, 962,963 cardiovascular diseases, 564,964 musculoskeletal diseases, [965][966][967][968] inflammatory diseases, 969,970 and Chagas disease (Trypanosoma cruzi infection). 971 Bifunctional antibody-ligand traps containing the extracellular domain of TβRII can target both TGF-β and immune checkpoints.…”