“…It has been reported that Smad3 knockout (TGFbeta deficient) mice display OA phenotypes. The gene profiling and PCR examination showed that BMP signaling pathways involving Smad-1, Smad-5, BMP-2, and BMP-6, were more active in Smad3 knockout chondrocytes (169), suggesting a shift from TGF-beta toward BMP signaling. Thus, as an extracellular BMP inhibitor, noggin could abrogate its maturation (170).…”
“…It has been reported that Smad3 knockout (TGFbeta deficient) mice display OA phenotypes. The gene profiling and PCR examination showed that BMP signaling pathways involving Smad-1, Smad-5, BMP-2, and BMP-6, were more active in Smad3 knockout chondrocytes (169), suggesting a shift from TGF-beta toward BMP signaling. Thus, as an extracellular BMP inhibitor, noggin could abrogate its maturation (170).…”
“… 199 , 214 Abolished TGF-β activity also alters IGF and FGF signaling and upregulates the expression of biosynthesis-related genes and electron transport chain-related genes, contributing to chondrocyte hypertrophy. 215 Our work showed that Runx1 protects cartilage homeostasis through promoting TGF-β signaling. 216 Fig.…”
Section: Tgf-β and Bmp Signaling In Articular Cartilage Homeostasismentioning
Transforming growth factor-βs (TGF-βs) and bone morphometric proteins (BMPs) belong to the TGF-β superfamily and perform essential functions during osteoblast and chondrocyte lineage commitment and differentiation, skeletal development, and homeostasis. TGF-βs and BMPs transduce signals through SMAD-dependent and -independent pathways; specifically, they recruit different receptor heterotetramers and R-Smad complexes, resulting in unique biological readouts. BMPs promote osteogenesis, osteoclastogenesis, and chondrogenesis at all differentiation stages, while TGF-βs play different roles in a stage-dependent manner. BMPs and TGF-β have opposite functions in articular cartilage homeostasis. Moreover, TGF-β has a specific role in maintaining the osteocyte network. The precise activation of BMP and TGF-β signaling requires regulatory machinery at multiple levels, including latency control in the matrix, extracellular antagonists, ubiquitination and phosphorylation in the cytoplasm, nucleus-cytoplasm transportation, and transcriptional co-regulation in the nuclei. This review weaves the background information with the latest advances in the signaling facilitated by TGF-βs and BMPs, and the advanced understanding of their diverse physiological functions and regulations. This review also summarizes the human diseases and mouse models associated with disordered TGF-β and BMP signaling. A more precise understanding of the BMP and TGF-β signaling could facilitate the development of bona fide clinical applications in treating bone and cartilage disorders.
“…Aberrant Rac1 activation has been identified in human OA cartilage ( Zhu et al., 2015 ). Cdc42 signaling pathways are enhanced in chondrocytes prone to promoting OA ( Wang et al., 2007 ). In addition, Cdc42 increases extracellular signal-regulated kinase 1/2 (ERK1/2) activation to activate SMADs, thus leading to subchondral bone remodeling in vivo ( Hu et al., 2018 ).…”
Section: Rho Gtpases In Rheumatic Diseasesmentioning
Summary
Rho guanosine triphosphatase (GTPases), as molecular switches, have been identified to be dysregulated and involved in the pathogenesis of various rheumatic diseases, mainly including rheumatoid arthritis, osteoarthritis, systemic sclerosis, and systemic lupus erythematosus. Downstream pathways involving multiple types of cells, such as fibroblasts, chondrocytes, synoviocytes, and immunocytes are mediated by activated Rho GTPases to promote pathogenesis. Targeted therapy via inhibitors of Rho GTPases has been implicated in the treatment of rheumatic diseases, demonstrating promising effects. In this review, the effects of Rho GTPases in the pathogenesis of rheumatic diseases are summarized, and the Rho GTPase-mediated pathways are elucidated. Therapeutic strategies using Rho GTPase inhibitors in rheumatic diseases are also discussed to provide insights for further exploration of targeted therapy in preclinical studies and clinical practice. Future directions on studies of Rho GTPases in rheumatic diseases based on current understandings are provided.
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