Where To Buy Bmp For Arthritis
Hong Jun Wang received her Ph.D. from McGill University, Canada, where she studied the function and regulation of a new histone deacetylase 4 (HDAC4). Dr. Wang started her postdoctoral training with Dr. Rik Derynck at UCSF, studying histone modification in TGF-beta/SMAD3 repressed muscle differentiation. She also studied the regulation of TGF-beta and BMP signaling pathways by protein arginine methylation of SMAD6. Dr. Wang continued her postdoctoral research with Dr. Vittorio Sartorelli at the NIAMS, focusing on transcriptional regulation of skeletal muscle differentiation and embryonic stem cell pluripotency and self-renewal. In 2016, she moved to the NIDCD as a contractor working on restoring genetic hearing loss by AAV-delivered CRISPR/Cas9 system. Dr. Wang returned to the NIAMS in 2020, and currently works with Dr. Sartorelli as a biologist in the Laboratory of Muscle Stem Cells and Gene Regulation.
where to buy bmp for arthritis
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases.
There are three TGF-βs: TGF-β1, TGF-β2, and TGF-β3 in mammals.2 TGF-βs elicit their cellular response via binding to a tetrameric receptor complex comprising two TGF-β type I receptors (TβRI/ALK5) and two type II kinase receptors (TβRII)2 (Figure 1). TβRII transphosphorylases TβRI resulting in subsequent phosphorylation of receptor-activated Smads (R-Smads), Smad2 and 3 (Figure 1).2 R-Smads then interact with the common Smad (Co-Smad), Smad4, and translocate into the nucleus, where they recruit co-factors to regulate gene (for example, CREB-binding protein (CBP) or p300) transcription.2 Recent studies have revealed that TGF-βs can also activate another group of R-Smad (Smad1, 5, and 8) via binding to ALK1.17,20 As an alternative non-Smad-dependent pathway, TGF-β also activates kinase 1 (TAK1) and TAK1-binding protein 1 (TAB1) which in turn initiates the MKKs (MAPK pathway member-encoding genes kinases)-p38 MAPK or -Erk (extracellular signal-regulated kinase) signaling cascade (Figure 1).4
Previous studies showed that TGF-β, through Alk5-Smad2/3 or Alk5-MAPK signaling, promotes osteoblast progenitor enrichment and early differentiation, but negatively regulates osteoblast differentiation and mineralization at latter stages. TGF-β is also a molecule coupling bone formation with bone resorption. The relationship between TGF-β and cartilage is more complex. Either loss of TGF-β or excessive active TGF-β contributes to the progress of osteoarthritis. Further studies will elucidate how TGF-β dose-dependently and stage-dependently regulates cartilage integrity. Those findings would facilitate the design of therapeutic approaches for targeting TGF-β in OA treatment.
BMPs have dual functions in regulating Wnt signaling. BMP induces Dkk1 and Sost expression through MAPK and Smad signaling, respectively, via BMPRIA to inhibit Wnt signaling in osteoblast, and negatively regulated bone mass.96,98 Smad4 competitively binds β-catenin and prevents its binding with Tcf/Lef transcription complex.123 Thus, ablation of Smad4 either in the crest neuron stem cell or in osteoblast results in upregulation of canonical Wnt signaling so as to promote bone formation.60,123 BMP2-induced formation of Smad1-Dvl1 complex also restricts β-catenin and inhibits its activity.197 On the other hand, BMPs stimulate osteoblast and chondrocyte differentiation synergistically with Wnt signaling. BMP-2 promotes canonical Wnt signaling by inducing Wnt3a, Wnt1, Lrp5 expression and inhibiting the expression of β-TrCP, the F-box E3 ligase was found responsible for β-catenin degradation in osteoblasts.198,199 Ablation of Smad4 in the pre-osteoblasts depletes LRP5 expression and impairs both BMP and Wnt signaling.123 BMP-2-induced LRP-5 expression also contributes to chondrocyte hypertrophy and osteoarthritis progress.200 Osteoblastogenesis is maximized in the presence of both BMP and Wnt signaling.198,201,202 Smad and TCF/LEF/β-catenin cooperatively complex with each other on the promoter to achieve the highest expression of osteoblast genes (Dlx5, Msx2, and Runx2).202 Moreover, activation of Wnt signaling by Wnt3a or overexpression of β-catenin/TCF4 promotes BMP signaling by stimulating BMP2 transcription.203
BDA2 is characterized by hypoplasia of the second middle phalanx of the index finger and sometimes the little finger.234 Inactivating mutations of Bmpr1b gene (for example, I200K, R486K, and R486Q)235,236 or GDF5 gene (for example, L441P and R380Q)237,238 were reported in BDA2 patients. Dathe et al.239 reported another genetic cause of BDA2: duplication of a regulatory element downstream of BMP2 repressed BMP2 expression. GDF5 mutations were also found to be the cause of a number of cartilage disorders, including symphalangsism,238 chondrodysplasia,240 and osteoarthritis.16
To sum up, mutations in the BMP and TGF-β signaling-related genes result in multiple inheritable bone diseases in humans, including ossification disorders, joint diseases, and skeleton developmental defects. In the future, more molecules or peptides targeting BMP and TGF-β signaling will be developed to treat genetic bone disorders, fracture healing, and osteoarthritis diseases.
BMP and TGF-β signaling pathways have important roles in skeletal development and postnatal skeleton homeostasis, by crosstalking with multiple signaling pathways, such as Wnt, Hedgehog, Notch, and FGF. Our understanding of BMP and TGF-β signaling is advanced with the generation of related mouse models, heritable human disease genetic studies and other new technologies including high-throughput screening. Specificity and versatility of BMP and TGF-β signaling are controlled by various ligand-receptor combinations, and transduced by co-Smad/R-Smad complex or MAPK cascade. The signaling is also dedicatedly controlled by factors including extracellular cognate binding proteins, I-Smad, epigenetic factors, and microRNA. Disruption of BMP and TGF-β signaling results in various bone disorders, such as osteoarthritis, FOP and Myhre syndrome. Manipulating BMP and TGF-β signaling pathways possess clinical implications for the treatment of multiple bone diseases including fracture healing, osteoarthritis, osteoporosis, and FOP. So far, BMP-2-and BMP-7-containing osteogenic implants have been used in over one million patients worldwide for the treatment of long bone nonunions, spinal fusions, and acute fractures. More importantly, with the aging population expected to double over the next decade, the number of patients suffering from osteoarthritis and osteoporosis is likely to increase dramatically and so is the cost of Medicare. Thus, it is compelling to elucidate the pathophysiology and the molecular mechanisms underlying skeleton health and bone diseases. Further, TGF and BMP signaling study will provide significant insights into the mechanism underlying how TGF and BMP signaling regulates osteoblast and chondrocyte proliferation, differentiation, maturation and activity in bone and cartilage formation, under both physiological and pathological condition (for example, osteoarthritis, osteoporosis, and bone cancer metastases. This study will also facilitate the design of novel therapeutic approaches for bone diseases.
Two families of signaling proteins represent valuable targets for human diseases associated with defects in bone and cartilage development. Yi-Ping Li and colleagues at the University of Alabama at Birmingham have reviewed how pathways activated by transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) help coordinate the development and maintenance of the skeletal system. TGF-β and BMP can promote both the construction and disassembly of bone and cartilage, and modulate the behavior of cells that form these tissues. The outcomes resulting from pathway activation are shaped by interactions between further signaling proteins and other cellular pathways, and diverse other regulatory mechanisms. Treatments targeting these activated pathways have already shown promise for repairing fractures and other bone damage, and evidence suggests that patients with osteoarthritis and other skeletal disorders may benefit from similar approaches.
The major focus of our group is the target-based design of novel anti-cancer and anti-rheumatoid arthritis chemotherapeutics. Currently we are focusing our efforts on the development of potent and selective inhibitors of enzymes whose activities are involved in modulating chromatin structure. The modulation of chromatin structure can have drastic effects on the transcription of particular genes. Our lab uses kinetic and structural analyses to guide the design of small molecule inhibitors, which we then synthesize and evaluate as inhibitors of these enzymes.
Protein Arginine Deiminases (PADs) catalyze the deimination of Arginine residues to citrulline in a number of proteins including histones H2A, H3, and H4. We are focused on developing inhibitors targeting these enzymes because their activity is aberrantly upregulated in numerous diseases, including cancer, colitis, and rheumatoid arthritis.
Protein levels of Wnt3a and β-catenin were increased, and collagen II was reduced in rat models of normal exercise-induced OA and injured exercise-induced OA groups [7]. Further study demonstrated that activation of β-catenin signaling in specific chondrocytes of adult mice resulted in the development of an OA-like phenotype [8]. Subsequently, transgenic mice with conditional activation of β-catenin signaling in Col2a1- or Agc1-expressing cells were shown to exhibit severe cartilage degeneration, subchondral bone erosion, and osteophyte formation [9]. Similarly, excessive WNT activation following loss of function of the WNT inhibitor Frizzled-related protein FRZB (also called secreted Frizzled-related protein 3, sFRP-3) resulted in increased susceptibility to OA in both humans [10] and mice [11]. In contrast, inhibition of β-catenin signaling in articular chondrocytes resulted in articular cartilage destruction [12], and excessive WNT suppression due to tumor necrosis factor (TNF)-dependent expression of DKK1 in inflammatory arthritis resulted in cartilage and bone destruction [13, 14]. Wnt16-deficient mice developed more severe osteoarthritis with increased chondrocyte apoptosis and reduced expression of lubricin [15], a chondroprotective agent that protects chondrocyte against mechanical damage. 041b061a72