Twisted Gastrulation-1 (TSG or TWSG1) is a cysteine-rich 24 kDa secreted glycoprotein that regulates BMP signaling (1, 2). It was initially identified for its role in dorsal/ventral patterning in Drosophila and Xenopus (1). Mouse TSG cDNA encodes 223 amino acids (aa) including a 25 aa signal peptide and a 198 aa mature protein with a cysteine-rich region (aa 26 ‑ 77) that interacts with BMPs and a C-terminal binding site for chordin (1, 3). Mouse TSG shares 98% aa identity with human, rat, canine, equine, bovine and porcine TSG. TSG can act as either an antagonist or an agonist for BMP signaling (1 ‑ 10). As an antagonist, the N-terminal domain of TSG can bind and inhibit BMP proteins directly, interfering with BMP receptor binding and activity (1, 4). Formation of a complex of TSG with chordin further enhances BMP inhibition (1, 4). As a BMP agonist, TSG promotes TLL-1 metalloproteinase cleavage of chordin to fragments that no longer inhibit BMP activity (3, 5). TSG effects on chordin are influenced by its concentration (2). TSG is widely expressed in the mouse embryo, and is co‑expressed with chordin and BMPs 2, 4 and 7 in the developing limbs (1). Mice lacking TSG show varying degrees of abnormality in bone, cartilage, forebrain, thymus and spleen, in part dependent on the mouse background (2, 5 ‑ 8). In bone, TSG participates with crossveinless-2 (CV-2) to create BMP activity gradients and limit osteoclast differentiation (6, 7). Postnatally, TSG is strongly expressed in growth plate cartilage where it limits collagen expression and enhances osteoblast differentiation and endochondral ossification (2, 4). TSG also modulates BMP and TGF-beta signaling in thymocytes, T cells and early erythrocytes (9 ‑ 11).