The interplay between Angiogenesis, Hypoxia and inflammation in rheumatoid hand disease

Abstract

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory condition affecting 1- 3% of the world population. Half of all patients with RA have tendon involvement. This often leads to multiple tendon ruptures. Tendon rupture is a strong indicator of poor, longterm, hand function. When tendons rupture, painful reconstructive surgery is currently the only way of restoring useful hand function. Patients with RA also develop characteristic deformities which often interfere with hand function. These include swan-neck, boutonniere and ulnar drift deformities. In particular, the development of ulnar drift in RA hands has always been very difficult to explain and is equally difficult to correct surgically. Local hypoxia and angiogenesis are recognised as key events which may initiate and perpetuate joint destruction in RA. More recently, they have also been shown to be important in tendon rupture. Previous studies carried out by our group used a microelectrode technique to demonstrate that invasive tenosynovium in RA patients is markedly hypoxic compared to tenosynovium in patients without RA. The results of these studies led us to conclude that hypoxia plays a key role in initiating and perpetuating tendon destruction in the same way that hypoxia affects RA joints. Therefore, my research set out to investigate the role of tissue hypoxia in tendon rupture in more detail. To further investigate the effects of hypoxia in RA, synovial tissue was harvested and cultured under either hypoxic (1% O2) or normoxic (21% O2) conditions. Under hypoxic conditions, I observed a significant upregulation of the matrix metalloproteinases (MMP) responsible for collagen breakdown. This upregulation was inhibited in the presence of a universal blocker for MMP. The expression of angiogenic stimuli such as vascular endothelial growth factor was also increased and crucially, my data showed that hypoxia increases the angiogenic drive of RA cells, as demonstrated by enhanced blood vessel formation in an in-vitro angiogenesis functional assay. In this way, I was able to show that hypoxia creates a stimulus for RA tenosynovium which is proangiogenic and proinvasive facilitating the tendon ruptures observed in RA. This has not previously been demonstrated. Intrinsic muscle dysfunction has been suggested as one of the mechanisms for the development of ulnar drift in RA hands. To investigate the possible link between hypoxia and ulnar drift, I speculated that the weakness and dysfunction of the intrinsic muscles observed in RA hands may also be due to hypoxia. Direct measurement of tissue oxygen in the intrinsic muscles of the RA hand has never been performed. Using our microelectrode technique, I found that the intrinsic muscles of RA patients undergoing elective surgery (n=30) are significantly more hypoxic than the intrinsic muscles of patients without RA (n=30). Within the RA group, I also observed a spatial trend for increasing hypoxia in the intrinsic muscles going from radial to ulnar. There was a further trend for increasing hypoxia moving from proximal to distal in the upper limb. My data confirmed that the intrinsic muscles are the most hypoxic. Therefore, it seems possible that hypoxia may at the very least contribute to the intrinsic muscle contracture and atrophy which are commonly observed in the RA hand. In so doing, intrinsic muscle hypoxia may contribute to the development of ulnar drift and the other deformities in the hand of RA patients. These findings have also never been demonstrated before. Many of the drugs currently used to treat RA (including anti-TNFα drugs) fail to prevent inflammation of the tenosynovium in the hand in a significant proportion of patients. We are also unaware of any treatments to block, reverse or ameliorate the effects of chronic muscle hypoxia. These findings may explain why many of the disabling effects of RA often continue despite otherwise adequate control of pain and other symptoms, especially in the hand. This study represents a further step forward on the path to understanding the debilitating effects of RA in the hand and may lead to the development of new treatments to prevent them