Thbs1, short for thrombospondin-1, is a secreted matricellular protein encoded by the THBS1 gene. It plays crucial roles in regulating cellular attachment dynamics and extracellular matrix protein production. Thbs1 is involved in multiple pathways such as the endoplasmic reticulum stress-related PERK-ATF4 pathway, TGFβ-Smad2/3-ATF4 pathway, and is associated with angiogenesis, antitumor immunity, and cell migration [1,3,4]. Genetic models, like KO mouse models, have been instrumental in studying its functions.

In Thbs1 -/- mice, several phenotypes have been observed. In the heart, Thbs1 -/- mice develop greater cardiac hypertrophy with pressure overload stimulation and show reduced fasting-induced atrophy, indicating that Thbs1 negatively regulates cardiac hypertrophy and promotes atrophy [1]. In skeletal muscle, Thbs1 -/- mice have significantly reduced levels of denervation-and caloric restriction-mediated muscle atrophy, along with blunted TGFβ-Smad3-ATF4 signaling, suggesting Thbs1's role in muscle atrophy regulation [3]. In colorectal cancer, loss of THBS1 in the tumor microenvironment renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs, highlighting its importance in cancer immunity [2].

In conclusion, Thbs1 is a key regulator in multiple biological processes. Its functions in the heart, skeletal muscle, and cancer-related immunity have been well-demonstrated through gene-knockout mouse models. These studies provide insights into potential therapeutic targets for heart muscle-related diseases, muscle atrophy-based diseases, and colorectal cancer treatment.

References:

1. Vanhoutte, Davy, Schips, Tobias G, Vo, Alexander, Sargent, Michelle A, Molkentin, Jeffery D. 2021. Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy. In Nature communications, 12, 3928. doi:10.1038/s41467-021-24215-4. https://pubmed.ncbi.nlm.nih.gov/34168130/

2. Omatsu, Mayuki, Nakanishi, Yuki, Iwane, Kosuke, Moscat, Jorge, Seno, Hiroshi. 2023. THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer. In Nature communications, 14, 5534. doi:10.1038/s41467-023-41095-y. https://pubmed.ncbi.nlm.nih.gov/37749092/

3. Vanhoutte, Davy, Schips, Tobias G, Minerath, Rachel A, Adams, Christopher M, Molkentin, Jeffery D. 2024. Thbs1 regulates skeletal muscle mass in a TGFβ-Smad2/3-ATF4-dependent manner. In Cell reports, 43, 114149. doi:10.1016/j.celrep.2024.114149. https://pubmed.ncbi.nlm.nih.gov/38678560/

4. Isenberg, Jeffrey S, Roberts, David D. . THBS1 (thrombospondin-1). In Atlas of genetics and cytogenetics in oncology and haematology, 24, 291-299. doi:10.4267/2042/70774. https://pubmed.ncbi.nlm.nih.gov/33244322/