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  • TGF-beta pathway inhibition as the therapeutic acceleration of diabetic bone regeneration.

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

Journal of orthopaedic research : official publication of the Orthopaedic Research Society (2021-11-15)
Mustafa Becerikli, Felix Reinkemeier, Mehran Dadras, Christoph Wallner, Johannes M Wagner, Marius Drysch, Alexander Sogorski, Maxi von Glinski, Marcus Lehnhardt, Stephan A Hahn, Björn Behr
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.

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Anti-TGF β2, C-Terminal antibody produced in rabbit, affinity isolated antibody