Gremlin, also known as Drm, is a highly conserved 20.7-kDa, 184 amino acid glycoprotein part of the DAN family and is a cysteine knot-secreted protein ^[1][2]. Gremlin was first identified in differential screening as a transcriptional down-regulated gene in v-mos-transformed rat embryonic fibrolasts^[3].

Gremlin 1 (grem 1) is known for its antagonistic reaction with bone morphogenetic proteins (BMPs) in the TGF beta signaling pathway. Grem 1 inhibits BMP-2, -4, and -7. Inhibition by grem 1 of BMPs in mice allow the expression of fibroblast growth factors (FGFs) 4 and 8 and Sonic hedgehog (SHH) which are necessary for proper limb development ^[4]. Grem 1 regulation of BMP-4 in mice embryos is essential in kidney and lung branching morphogenesis ^[5][6].

Data from microarrays of cancer and non-cancer tissues suggest that grem1 and other BMP antagonists are important in the survival of cancer stroma survival and proliferation in some cancers ^[7]. Grem 1 expression is found in many cancers and is thought to play important roles in uterine cervix, lung, ovary, kidney, breast, colon, pancreas, and sarcoma carcinomas. More specifically, the grem 1 binding site (between residues 1 to 67) interacts with the binding protein, YWHAH (whose binding site for grem1 is between residues 61-80) and is seen as a potential therapeutic and diagnostic target against human cancers ^[8]. Grem 1 also plays a BMP-dependent role in angiogenesis on endothelium of human lung tissue, which implies an important role for grem 1 in the development of cancer ^[9].

Deletion of grem 1 in mice causes increased bone formation and increased trabecular bone volume where overexpression causes inhibition of bone formation and osteopenia ^[10][11]. Deletion of one copy of grem1 does not produce an abnormal phenotype and deletion of both copies causes only a small differnce in phenotype in one month old male mice, but this difference cannot be observed after 3 months of age ^[12]. Grem1 plays an important role in bone development and a lesser known function later in adulthood. Overexpression of gremlin 1 decreases osteoblast differentiation or the inhibition of bone formation and the ability for bone remodeling ^[13]. Overexpression of grem1 in stromal and osteoblastic cells in addition to the inhibition of BMP, grem 1 inhibits activation Wnt/β-catenin signaling activity. The interaction between grem 1 and the Wnt signaling pathway is not fully understood ^[14].

-Gazzero E, Pereira RC, Jorgetti V, Olson S, Economides AN, Canalis E (2005). "Skeletal overexpression of gremlin impairs bone formation and causes osteopenia". Endocrinology 142(2):655-665.

-Gazzero E, Smerdel-Ramoya A, Zanotti S, Stadmeyer L, Durant D, Economides AN, Canalis E (2007). "Conditional deletion of gremlin causes a transient increase in bonformation and bone mass". Journal of Biological Chemistry 282(43):31549-31557.

-Michos O, Goncalves A, Lopez-Rios J, Tiecke E, Naillat F, Beier K, Galli A, Vainio S, Zeller R (2007). "Reduction of BMP4 activity by gremlin 1 enables ureteric bud outgrowth and GDNF/WNT11 feedbak signalling during kidney branching morphogenesis". Development 134:2397-2405.

-Namkoong H, Shin SM, Kim HK, Ha S, Cho GW, Hur SY, Kim TE, Kim JW (2006). "The bone morphognentic protein antagonist gremlin 1 is overespressed in human cancers and interacts with YWAHAH protein". BMC cancer 6:74.

-Shi W, Zhao J, Anderson KD, Warburton D (2001). "Gremlin negatively modulated BMP-4 induction of embryonic mouse lung branching morphogenesis". Am J Physiol Lung Cell Mol Physiol 280:L1030-L1039.

-Sneddon JB, Zhen HH, Montgomery K, van de Rijn M, Tward AD, West R, Gladstone H, Chang HY, Morganroth GS, Oro AE, Brown PO (2006). "Bone morphogenetic protein antagonist gremlin 1 is widely expressed y cancer-associated stromal cells and can promote tumor cell proliferation". PNAS 103(40):14842-14847.

-Stabile H, Mitola S, Moroni E, Belleri M, Nicoli S, Coltrini D, Peri F, Pessi A, Orsatti L, Talamo F (2007). Blood 109(5):1834-1840.