Mast cells and hypoxia drive tissue metaplasia and heterotopic ossification in idiopathic arthrofibrosis after total knee arthroplasty.

Freeman TA, Parvizi J, Dela Valle CJ,and Steinbeck MJ. Fibrogenesis Tissue Repair. 2010; 3: 17.

This is the editor's interpretation of a paper published in the orthopaedic literature in 2011 - our attempt to make relevant medical articles accessible to lay readers. If you wish to read the original it is easy to ask your librarian to obtain a reprint for you from any medical library.

The word 'idiopathic' means that the cause is currently unknown. In this article the authors publish the results of their investigation into tissue samples taken from 10 patients with idiopathic arthrofibrosis, where they were trying to identify factors within the tissues themseves that may have triggered or contributed to the development of the arthrofibrosis. [Ed note: Arthrofibrosis is a condition of abnormal and excessive scarring within a joint, leading to stiffness of the joint.]

After total knee replacement 3-4% of patients may go on to develop arthrofibrosis, but the authors state that at the time of this publication (2010) there is no definite way of identifying which patients are at risk of developing this this nasty complication. In a previous publication (and in common with other investigators), however, they previously published that they had found in their arthrofibrotic patients the presence of aggressive fibroblasts and heterotopic ossification. [Ed note: Fibroblasts are cells in the body that produce fibrous tissue, found normally but also the main component of scar tissue. Heterotopic ossification is the formation of abnormal bone tissue within soft tissues where bone would not normally be found.] Around the areas of aggressive fibroblast activity they found that the cells had secreted an excess of 'extracellular matrix' - the kind-of cement that helps to hold the tissues together as they form, and that this abnormal matrix in these areas was such that it was blocking blood flow and oxygen delivery in those areas. The poor oxygen delivery (called 'hypoxia') in turn triggered the release of enzymes and the attraction of other fibrous cells from the blood vessels.

They point out that laboratory experiments have demonstrated that under conditions like this fibrous cells (fibrocytes) can change their nature, and become more like cartilage cells (chondrocytes). They also say that they and other workers have found that such conditions can also stimulate mast cells (which normally have a role in immunity, protecting the body from outside threats) to proliferate and produce abnormal enzymes of their own, which further trigger the laying down of more fibrous cells and more abnormal matrix, thus aggravating the hypoxia.

When cells change and take on abnormal roles like this it is called 'metaplasia'. The authors undertook this study to try and further understand the cell metaplasia occurring in arthrofibrosis. Their 10 patients who had developed arthrofibrosis after knee replacement were matched with 10 who had also had the same procedure but had not developed this problem. They took the tissue samples of the arthrofibrotic material and subjected it to 'microCT' scanning.  [Ed note: This is using computer software to examine tiny 'X-ray slices' of the tissues.]

They found on the microCT scans -

  • all 10 patients with the arthrofibrosis had mineralised material in their tissue samples with a density like that of bone
  • 5 of the 10 had extensive amounts of actual bone in their tissue samples

When they looked, however, at proper X-rays of these patients' knees, they could not see anything wrong, and could not see anything that looked like heterotopic ossification. They then looked at other measures, comparing the two patient groups, and an important finding was that the patients whose samples were showing abnormal bone formation(even though their X-rays were not) had reduced range of motion  (ROM) of their knees. Patients with less than 50 degrees of ROM had higher amounts of abnormal bone in their microCT scans. The lower the ROM, the higher the amount of abnormal bone in the tissue specimens.

They also further investigated the tissue samples, examining the cells in the areas with the bony change, and comparing them with cells in the same sample where there was no bony change and also to samples from patients who had not developed arthrofibrosis (taken at the time of the initial knee replacement. The abnormal areas predictably had poor vascularity (blood vessels) increased density of fibrous cells and mast cells, and the greater the degree of bony change the higher the number of mast cells. Their conclusion is that "that hypoxia, hypoxia-associated oxidative stress, and mast cells drive the proliferation and survival of fibroblasts and their metaplastic conversion to fibrocartilage, which, through the process of endochondral ossification, results in heterotopic bone formation" [Ed note: That means "decreased oxygen supply, and the stress that this causes to the tissues, together with substances released from mast cells drives this whole abnormal process, triggering fibrous cells to both proliferate and to abnormally change themselves into fibro-cartilage cells, which then further change to result in abnormal bone formation.]

The authors went on to discuss what might be done to prevent patients developing arthrofibrosis after knee replacement, and suggestions included interventions to increase blood flow such as physical manipulation and/or low dose irradiation.