Methods and compositions for use in modulating the activity(s) of WISP-1 polypeptide are provided. WISP-1 antagonists include anti-WISP-1 antibodies, WISP-1 immunoadhesins and WISP-1 variants (and fusion proteins thereof) which inhibit or neutralize induction or secretion of HAS2, HA, CD44 or RHAMM by native human WISP-1 polypeptide in at least one type of mammalian cell. The invention also provides methods for in vitro, in situ, and/or in vivo diagnosis and/or treatment of mammalian cells or pathological conditions associated with native WISP-1 polypeptides.