Publications

Osteopontin is an adhesive glycoprotein implicated in numerous diseases associated with inflammation and remodeling. There are several structural domains in osteopontin that are of particular interest. The RGD motif is a cell attachment sequence shown to be critical for cell adhesion through alphav-containing integrins. In close proximity to the RGD domain is the thrombin cleavage site. Previous observations suggest that thrombin cleavage of osteopontin occurs in vivo and may be physiologically important. To study the functional significance of osteopontin cleavage by thrombin, we made glutathione S-transferase-osteopontin fusion proteins. These proteins contain either the N- or C-terminal domains expected to be formed following thrombin cleavage at the Arg169-Ser170 peptide bond. We compared these osteopontin fragments with native osteopontin in their ability to support adhesion of several different cell lines and identified the receptors mediating these interactions. Our data show that the N-terminal osteopontin fragment, which contains the RGD domain, supports adhesion of a melanoma cell line that is unable to bind native osteopontin. This suggests that osteopontin adhesive interactions may be regulated by thrombin cleavage. We also demonstrate that osteopontin contains a cryptic binding activity, which can be recognized by a novel osteopontin receptor. This receptor has been identified as the alpha9beta1 integrin.

BACKGROUND

Valvular heart disease is the most important cardiac manifestation of systemic lupus erythematosus. We performed a study to determine the relation of valvular disease to other clinical features of lupus, whether or not the valve disease progresses, and the associated morbidity and mortality.

METHODS

We performed transesophageal echocardiography and rheumatologic evaluations in 69 patients with systemic lupus erythematosus. The echocardiographic findings were compared with those in 56 healthy volunteers. Fifty-eight patients (84 percent) had second evaluations a mean (+/-SD) period of 29 +/- 13 months later. The patients and controls were followed for 57 months.

RESULTS

Valvular abnormalities were common on the initial and the follow-up echocardiograms (in 61 and 53 percent of the patients, respectively). Valvular thickening was the predominant finding initially and on follow-up (in 51 and 52 percent of the patients, respectively), followed by vegetations (in 43 and 34 percent), valvular regurgitation (in 25 and 28 percent), and stenosis (in 4 and 3 percent). Valvular abnormalities frequently resolved, appeared for the first time, or persisted but changed in appearance or size between the two studies. Mild or moderate valvular regurgitation did not progress to become severe, and new stenoses did not develop. Neither the presence of valvular disease nor changes in the echocardiographic findings were temporally related to the duration, activity, or severity of lupus or to its treatment. The combined incidence of stroke, peripheral embolism, heart failure, infective endocarditis, and the need for valve replacement was 22 percent in the patients with valvular disease, but only 8 percent in those without it. A total of seven patients died during follow-up, in most cases as a result of valvular disease. Valvular abnormalities and complications were uncommon in the controls (occurring in 9 and 2 percent, respectively).

CONCLUSIONS

Valvular heart disease is common in patients with systemic lupus erythematosus, frequently changes over time, appears to be temporally unrelated to other clinical features of lupus, and is associated with substantial morbidity and mortality.