||SPARC, an acronym for “secreted protein, acidic and rich in cysteine”, is also known as osteonectin or BM40. It is the founding member of a family of secreted matricellular proteins with similar domain structure. The 302 amino acid (aa), 43 kDa protein contains a 17 aa signal sequence, an Nterminal acidic region that binds calcium, a follistatin domain containing Kazallike sequences, and a Cterminal extracellular calcium (EC) binding domain with two EFhand motifs. Crystal structure shows that residues implicated in cell binding, inhibition of cell spreading and disassembly of focal adhesions cluster on one face of SPARC, while a collagen binding epitope and an Nglycosylation site are opposite this face. SPARC is produced by fibroblasts, capillary endothelial cells, platelets and macrophages, especially in areas of tissue morphogenesis and remodeling. SPARC shows contextspecific effects, but generally inhibits adhesion, spreading and proliferation, and promotes collagen matrix formation. For endothelial cells, SPARC disrupts focal adhesions and binds and sequesters PDGF and VEGF. SPARC is abundantly expressed in bone, where it promotes osteoblast differentiation and inhibits adipogenesis. SPARC is potentially cleaved by metalloproteinases, producing an angiogenic peptide that includes the copperbinding sequence KGHK. Paradoxically, SPARC is highly expressed in many tumor types, yet expression mainly decreases the likelihood of metastasis and confers sensitivity to chemotherapy and radiation. Stabilin1, which is expressed on alternately activated macrophages, is the first SPARC receptor to be identified. It binds the SPARC EC domain and mediates endocytosis for degradation. Mature mouse SPARC shows 97%, 92%, 92%, 92% and 83% aa identity with rat, human, dog, cow and chick SPARC, respectively.