Bone Morphogenetic Protein-5 (BMP-5) is one of at least 15 structurally and functionally related BMPs which are members of the transforming growth factor? beta (TGF-beta ) superfamily. BMP-5 is synthesized as a 452 amino acid (aa) precursor protein that is cleaved at the dibasic cleavage site (RxxR) to release the 20 kDa C-terminal mature protein. Mature BMP-5 contains seven conserved cysteine residues involved in formation of the cysteine knot and the single interchain disulfide bond. Biologically active BMP-5 is a disulfide-linked homodimer of the C-terminal mature protein. Mature mouse BMP-5 shares 96% and 99% aa sequence identity with human and rat BMP-5, respectively. Cellular responses to BMP-5 are mediated by the formation of hetero-oligomeric complexes of type?I and type?II serine/threonine kinase receptors. BMP-5 is expressed by chondrocytes in proliferating and hypertrophic zones of bone growth plates. It contributes to limb development by promoting proliferation and differentiation of chondrocytes as well as apoptosis of undifferentiated mesoderm. Genetic defects in BMP-5 which cause C-terminal truncation or loss of the proteolytic cleavage site result in multiple skeletal abnormalities, including the?short ear?phenotype in mice. BMP-5 is also expressed by ovarian granulosa cells where it functions as an autocrine factor to promote GC proliferation and inhibit their production of progesterone. In the nervous system, BMP-5 promotes dendrite outgrowth and dopaminergic neuronal differentiation. It is upregulated in oral squamous carcinoma cells and induces the apoptosis of some myeloma cell lines.