By days 5 and 10, TGF-beta 1 induced an increase in knee diameter and complete encasement of joints in dense scar-like tissue, locking joints at 90 degrees of flexion. Histologically, massive proliferation of synovial fibroblasts was seen, followed by their differentiation into myofibroblasts. The fibrotic tissue displaced the normal architecture of the joint capsule and fused with articular cartilage.
RNA expression profiles showed high levels of transcription of numerous MMPs, matricellular and ECM proteins. By day 30, the phenotype of the fibrotic tissue had undergone chondrometaplasia, indicated by cellular morphology, matrix composition and >100-fold increases in expression of collagen type II and cartilage link protein. Pre-labeling of articular cells by injection with recombinant lentivirus containing eGFP cDNA showed fibrotic/cartilaginous tissues appeared to arise almost entirely
from local proliferation check details and differentiation of resident fibroblasts. Altogether, these results indicate that TGF-beta 1 is a potent inducer of arthrofibrosis, and illustrate the proliferative potential and plasticity of articular fibroblasts. They suggest the mechanisms causing arthrofibrosis share many aspects with tumorigenesis. Laboratory Investigation (2010) 90, 1615-1627; doi:10.1038/labinvest.2010.145; published online 9 August 2010″
“Toll-like receptor-2 (TLR2) is a pivotal pathogen recognition receptor that has a key role in inflammation, diabetes, and injury. Hyperglycemia, inflammation, and oxidative stress induce TLR2-myeloid differentiation
factor-88 Copanlisib (MyD88) expression and signaling, and are major pathophysiological mechanisms in the impaired diabetic wound-healing process. The aim of the study was to examine the contribution of TLR2-MyD88 expression and signaling to the prolonged inflammation observed in diabetic wounds. Diabetes was induced in male C57BL/6J and TLR2(-/-) mice using streptozotocin (STZ) with matching nondiabetic mice as control. In addition, nonobese diabetic (NOD) mice were used to represent the spontaneous type 1 diabetes condition. After 2 weeks of persistent hyperglycemia in the mice, full-thickness excision wounds were made PCI-34051 on the backs aseptically. Total RNA and protein were subjected to real-time PCR and western blot analyses. Wound sizes were measured using digital planimetry. TLR2 mRNA and protein expression increased significantly in wounds of C57BL/6J + STZ and NOD mice (P<0.05) compared with nondiabetic C57BL/6J mice. MyD88 expression, interleukin receptor-associated kinase-1 phosphorylation, and nuclear factor-kappa B (NF-kappa B) activation were increased in diabetic wounds compared with nondiabetic wounds. Wounds of TLR2(-/-) + STZ mice showed less oxidative stress, decreased MyD88 signaling, NF-kappa B activation, and cytokine secretion. The wound closure was significant in TLR2(-/-) + STZ mice compared with C57BL/6J + STZ mice.