The biological activity loss of TGFb1 related cellular acti vation in BRONJ affected oral mucosa connective tissue could explain the prolonged wound healing and the lack of mucosal regeneration in BRONJ lesions. Indeed, this study confirmed the in vitro finding that collagens I and III expression decreased in oral mucosa fibroblasts fol lowing application of zoledronic acid. Our results suggested that in vivo stimulation of ECM protein deposition would most likely be inhibited, due to the increased expression of Smad 7, which inhibits TGFb1 activity. In contrast to skin and mucosa fibrosis, which is characterized by excessive Inhibitors,Modulators,Libraries expression of TGFb1 and Smad 23, accompanied by suppression of Smad 7, the BRONJ affected tissues were in a sclerotic state brought about by the imbalance in TGFb1 signaling.

The findings of this study provided evidence that the etio pathological development of BRONJ is different from other diseases that present exposed jaw bone. For exam ple, osteoradionecrosis has been Inhibitors,Modulators,Libraries shown to be associated with increased expression of TGFb1. This study showed that BRONJ adjacent soft tissue and osteoradio necrosis related mucoperiosteal tissue had differential impairments in TGFb1 related signaling. Osteoradione crosis affected tissues showed upregulation of TGFb1 and Smad 23 expression and suppression of Smad 7 this was the opposite of findings in BRONJ affected tissues. Oral mucosa morphology features a direct hemides mosomal connection between the periosteum and the basal lamina. This implies that connective tissue fibro blasts originate from periosteal progenitors.

There fore, BP related transdifferentiation of oral periosteal progenitor cells would be expected to influence the cel lular identity and proliferation Inhibitors,Modulators,Libraries of periodontal tissue stro mal cells. This suggestion was supported by the recent finding that Msx 1 expression was reduced in BP exposed periosteum. Moreover, impairment of the TGFb1 driven EMT in BRONJ sites led to both reduced re epithelization of the wound surface and altered differ entiation of connective tissue progenitors Vincent, 2009 3998. In osteoradionecrosis related mucoperiosteal tis sues, the overexpression Inhibitors,Modulators,Libraries of TGFb1 causes an arrest of the EMT process in activated myofibroblasts conversely, in BRONJ, the lack of TGFb1 and Smad 23 activity attenuated the stimulation of EMT Schultze Mosgau, 2004 2678.

In addition to suppressing cell proliferation, BPs have been shown in vitro to induce osseous differentiation in periosteal cells. Furthermore, BPs have been shown to enhance recruitment and differentiation of osseous progenitors in the periodontal ligamentum. Those findings suggested that a reduction of con nective tissue differentiation and increased osseous sti Inhibitors,Modulators,Libraries mulation are likely to occur during jaw periosteal and periodontal progenitor MDV3100 cell differentiation.