The word upon which the stress is placed, can alter the emphasis. "How ARE you?", for example, might be used if you hadn't seen a person for some time.
"What's up" could be very informal, or you might say to someone who appears upset, "What's up?" in place of "What's wrong? (with you, you seem upset?).
"What's the matter?" is similar to "What's wrong?" and would generally be used if you detect that the person is unhappy.
Generally, the latter two would be more appropriate for informal situations with people you know, although if a stranger seemed sad, you might ask them.
Usage is very context dependent in this case :-)