Myofibroblasts and their resistance to apoptosis: a possible mechanism of osteoradionecrosis

Lei Tian,¹ Li-Sheng He,¹ Bhavesh Soni,² Hong-Tao Shang<sup>1

1</sup>Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, China; ²Maxillofacial Unit, Morriston Hospital, Swansea, Wales, UK

Abstract: Osteoradionecrosis (ORN) in the head and neck area is the most devastating long-term complication of radiotherapy, with slow progression and inability to heal spontaneously. ORN can lead to intolerable pain, fractures, and sequestration of devitalized bone and fistulae, making oral feeding impossible and causing facial deformation. In spite of its notorious reputation over at least 90 years, the precise pathogenesis of ORN has not been fully clarified, which has led to obstacles in the management of the disease. Several theories about its pathogenesis have been formulated, and radiation-induced fibrosis is the newest one. According to this theory, ORN is essentially a type of fibrosis induced by radiotherapy, and antifibrosis therapy has been shown to be effective in its treatment. We assumed that ORN, like fibrosis in other organs, is the result of a process of fibrogenesis in which myofibroblasts are the key effector cells. The uninterrupted accumulation of myofibroblasts and consequent persistent excess production of collagenous extracellular matrix and tensile force result in loss of normal function and ultimately radiation-induced fibrosis. During this process, myofibroblasts may be protected from apoptosis by acquiring an immune-privileged capacity, which allows continuous matrix synthesis. If this hypothesis proves to be correct, it would enable better understanding of the cellular and molecular mechanisms underlying the pathogenesis and progression of ORN, and would help improve our ability to prevent occurrence of ORN, give an earlier diagnosis, and treat it more effectively.

Keywords: osteoradionecrosis, apoptosis, fibrosis, mandible, myofibroblast