From Longevity Wiki

Sostdc1 (Sclerostin domain-containing protein-1), also known as USAG-1 (uterine sensitization-associated gene 1), Ectodin and Wise (Wnt modulator in surface ectoderm)[1][2] is a member of the sclerostin family and encodes a secreted 28–32 kDa protein with a C-terminal cystine knot-like domain and two N-linked glycosylation sites. Sostdc1 functions as an antagonist to bone morphogenetic protein (BMP), mediating BMP signaling.[3] It also interacts with LRP6 (Low-density lipoprotein receptor-related protein 6), mediating LRP6 and canonical Wnt signaling, thus regulating cellular proliferation, differentiation, and programmed cell death. The canonical Wnt pathway, which stabilizes cytoplasmic β-catenin to activate its transcriptional response, marks and regulates stem cells in epithelial, stromal, and endothelial tissues in multiple organs, and is conserved across the animal kingdom from sponges to humans.[4]

Sostdc1 plays various roles in the skin, intestines, brain, lungs, kidneys, and vasculature. Deletion of Sostdc1 gene in mice resulted in supernumerary teeth[5] [6] and improved the loss of renal function.[7][8] In the skeletal system, Sostdc1 is essential for bone metabolism, bone density maintenance, and fracture healing.[9]

Prohibition on renewal of teeth in adults

Some animals, including sharks and some types of reptiles, are able to constantly generate new teeth. At the same time, humans can only grow two sets of teeth in a lifetime. Mice carrying mutations in Wise (Sostdc1) display defects in many aspects of tooth development, including tooth number, size and cusp pattern. Inactivation of Wise leads to elevated Wnt signaling and, as a consequence, vestigial tooth buds in the normally toothless diastema region display increased proliferation and continuous development to form supernumerary teeth.[10] It is possible to control the eruption of regenerated tooth with accurate morphology, adequate calcification, correct eruption timing and region by administration of anti- USAG-1 antibody.[6] The morphology of supernumerary teeth is depended on the position. If it erupts in the incisor or molar region, its shape is incisor or molar.[6] The clinical application of USAG-1-targeting antibodies to regenerate lost teeth requires further safety and efficacy validation in nonrodent models. In addition to antibodies to inhibit USAG-1, it may be possible to use a relatively cheap and non-toxic preparation designated as 6473.[11]

Renal interstitial fibrosis and vascular calcification

USAG-1 is the most abundant BMP antagonist in the adult kidney. USAG-1 can block the repair of renal injury by antagonizing BMP7.[8] The cellular distribution of USAG-1 is overlapping with that of BMP-7 in the kidney. Kidney development is severely delayed in BMP7-deficient mice and these mice generally die within a short period of time after birth. Multiple reports have demonstrated that BMP7 alleviates acute and chronic kidney injury, including by reducing apoptosis and necrosis of renal tubular epithelial cells (TECs), inhibiting the expression of inflammatory cytokines, reducing inflammatory cell infiltration, and reversing the progression of renal fibrosis.[8]

TGF-β1 (transforming growth factor-β1) upregulates the expression of USAG-1 and induces EMT (epithelial-mesenchymal transition) in canine kidney cells, whereas USAG-1 gene silencing with febuxostat prevents TGF-β1-induced EMT.[12]

Vascular calcification (VC) which is the pathological mineral deposition in the vascular system, predominantly at the intimal and medial layer of the vessel wall, is an important comorbidity in old patients, most of which have chronic kidney disease (CKD), leading to significant morbidity and mortality while necessitating appropriate treatment. However, it is not clear why aging is characterized by an increased calcification of the vessel wall.[13][14] Vascular calcific lesions associated with atherosclerosis, diabetes and chronic kidney disease are known to be enriched in BMP ligands.

Role of Sostdc1 in skeletal biology


Sostdc1 is a Paracrine Factor for Hair Follicle Growth

Hair follicle (HF) stem cells, which reside within the bulge region of the hair follicle (HF), promote the repetitive regeneration of the follicle during the hair cycle, wherein expression levels of Sostdc1 in lymphatic vessels (LVs) also undergo cyclic changes during the hair cycle. The mRNA expression levels of Sostdc1 in the back skin of female mice were significantly increased during the anagen phase (at day 12 after depilation), as compared with the telogen phase (at day 22 after depilation).[15] Sostdc1 markedly increased expression of Lef-1 a downstream target of Wnt signaling which is required for the development of the HFs. So, lymphatic vessels (LVs) may stimulate Hair follicle (HF) growth through Sostdc1 secretion.[15]

Sostdc1 plays an inhibitory role in tumourigenesis


  1. Itasaki, N., Jones, C. M., Mercurio, S., Rowe, A., Domingos, P. M., Smith, J. C., & Krumlauf, R. (2003). Wise, a context-dependent activator and inhibitor of Wnt signalling. Development, 130(18):4295-305 PMID: 12900447 DOI: 10.1242/dev.00674
  2. Valensi, M., Goldman, G., Marchant, D., Van Den Berghe, L., Jonet, L., Daruich, A., ... & Abitbol, M. M. (2019). Sostdc1 is expressed in all major compartments of developing and adult mammalian eyes. Graefe's Archive for Clinical and Experimental Ophthalmology, 257, 2401-2427. PMID: 31529323 DOI: 10.1007/s00417-019-04462-4
  3. Yanagita, M., Oka, M., Watabe, T., Iguchi, H., Niida, A., Takahashi, S., ... & Sakurai, T. (2004). USAG-1: a bone morphogenetic protein antagonist abundantly expressed in the kidney. Biochemical and biophysical research communications, 316(2), 490-500. PMID: 15020244 DOI: 10.1016/j.bbrc.2004.02.075
  4. Clevers, H., Loh, K. M., & Nusse, R. (2014). An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. science, 346(6205), 1248012. PMID: 25278615 DOI: 10.1126/science.1248012
  5. Murashima-Suginami, A., Takahashi, K., Sakata, T., Tsukamoto, H., Sugai, M., Yanagita, M., ... & Bessho, K. (2008). Enhanced BMP signaling results in supernumerary tooth formation in USAG-1 deficient mouse. Biochemical and biophysical research communications, 369(4), 1012-1016. PMID: 18329379 DOI: 10.1016/j.bbrc.2008.02.135
  6. 6.0 6.1 6.2 Murashima-Suginami, A., Kiso, H., Tokita, Y., Mihara, E., Nambu, Y., Uozumi, R., ... & Takahashi, K. (2021). Anti–USAG-1 therapy for tooth regeneration through enhanced BMP signaling. Science advances, 7(7), eabf1798. PMID: 33579703 PMC7880588 DOI: 10.1126/sciadv.abf1798
  7. Yanagita, M., Okuda, T., Endo, S., Tanaka, M., Takahashi, K., Sugiyama, F., ... & Sakurai, T. (2006). Uterine sensitization-associated gene–1 (USAG-1), a novel BMP antagonist expressed in the kidney, accelerates tubular injury. The Journal of clinical investigation, 116(1), 70-79. PMID: 16341262 PMC1307562 DOI: 10.1172/JCI25445
  8. 8.0 8.1 8.2 Li, X., Yue, W., Feng, G., & Li, J. (2021). Uterine sensitization-associated gene-1 in the progression of kidney diseases. Journal of Immunology Research, 2021, 1-6. PMID: 34414243 PMC8369194 DOI: 10.1155/2021/9752139
  9. 9.0 9.1 Tong, X., Zhu, C., Liu, L., Huang, M., Xu, J., Chen, X., & Zou, J. (2022). Role of Sostdc1 in skeletal biology and cancer. Frontiers in physiology, 2221. PMID: 36338475 PMCID: PMC9633957 DOI: 10.3389/fphys.2022.1029646
  10. Ahn, Y., Sanderson, B. W., Klein, O. D., & Krumlauf, R. (2010). Inhibition of Wnt signaling by Wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning. Development, 137(19), 3221-3231. PMID: 20724449 PMCID: PMC6512258 DOI: 10.1242/dev.054668
  11. Poorani R, Elakkiya E, & Gupta, K. K. (2022). USAG1 protein: An important drug target in teeth regeneration. bioRxiv, 2022-08.
  12. Lu, L., Zhu, J., Zhang, Y., Wang, Y., Zhang, S., & Xia, A. (2019). Febuxostat inhibits TGF‑β1‑induced epithelial‑mesenchymal transition via downregulation of USAG‑1 expression in Madin‑Darby canine kidney cells in vitro. Molecular Medicine Reports, 19(3), 1694-1704. PMID: 30628645 PMC6390060 DOI: 10.3892/mmr.2019.9806
  13. Kanbay, M., Copur, S., Tanriover, C., Yavuz, F., Galassi, A., Ciceri, P., & Cozzolino, M. (2023). The pathophysiology and management of vascular calcification in chronic kidney disease patients. Expert Review of Cardiovascular Therapy, 21(2), 75-85. PMID: 36716079 DOI: 10.1080/14779072.2023.2174525
  14. Castelli, R., Gidaro, A., Casu, G., Merella, P., Profili, N. I., Donadoni, M., ... & Delitala, A. P. (2023). Aging of the Arterial System. International Journal of Molecular Sciences, 24(8), 6910. PMID: 37108072 PMC10139087 DOI: 10.3390/ijms24086910
  15. 15.0 15.1 Yoon S-Y, Detmar M. (2022). Sostdc1 Secreted from Cutaneous Lymphatic Vessels Acts as a Paracrine Factor for Hair Follicle Growth. Current Issues in Molecular Biology. 44(5), 2167-2174. PMID: 35678675 PMC9164032 DOI: 10.3390/cimb44050146