Author and Reporter: Anamika Sarkar, Ph.D and Ritu Saxena, Ph.D.
Cartilage is the tissue lining of the joints and acts as a cushion between the joints. Osteoarthritis, a disease accompanied by severe pain and limitations of functions, is the result of degeneration of cartilage. Currently, such conditions of patients are considered irreversible and treatment options are mainly based on pain management and joint replacement therapy.
Some of these procedures are – Autologous Chondrocyte Implantation (ACI), Osteochondral Allograft Transplantation, Meniscal Transplantation. In these procedures, healthy cartilage (or meniscus in case of Meniscal Transplantation) are taken either from the patients or deceased donors and transplanted in the damaged joints for cartilage repair. (Please see information regarding cartilage repair, cartilage supplement in sources below).
Harnessing use of regenerative powers of stem cells have been recognized as alternative methods of treatments. Stem cells are the cells that have the capacity to develop into different cell types. They can continue to renew themselves with cell division without being differentiated. Moreover, with the right stimulus they can also be induced to differentiate into specialized cell types. Thus, with discovery and understanding of right stimuli and its signaling processes, stem cells can serve as a powerful candidate for repair of damaged tissues and organs.
Since, stem cells are precursor of many differentiated cell types, a lot of research is needed to determine the right conditions to direct the stem cell differentiation into the desired cell type for the purpose of treatment. Attempts have been made in the area of regenerative medicine for cartilage regeneration using stem cells. Kafienah et al (2007) bioengineered a three-dimensional cartilage using adult stem cells from the bone marrow of osteoarthritis patients. Although, this method could thus be used for repairing cartilage lesions, however, it needs to be implanted into the joint adding challenges to the development of therapy.
A very interesting study published in the recent issue of the journal Science (Johnson et. al., A Stem Cell-Based Approach to Cartilage Repair, Science, 336, p717,2012) described breakthrough discovery – a small molecule, Kartogenin (KGN), has the capability of promoting chondrocytes (cells which make healthy cartilage) differentiation.
The authors, Johnson et al. showed their finding of KGN as a stimulus for stem cell differentiation to chondrocytes in a systematic fashion. They used high throughput screening of images from 5 primary human stem cells derived from bone marrow in their in-vitro studies. Their results show when cells were treated with 100nM of KGN, they show regeneration of cartilage forming chondrocytes. They supported their finding in animal model using mice model by inducing Osteoarthritis and then treating them with KGN.
In order to make sure that KGN has a direct effect on the signaling of chondrocytes, Johnson et. al., showed activation of some of the key signaling components in the KGN stimulated chondrocytes pathway, using in-vitro studies. They showed that upon activation of cells with KGN, CBFb (core-binding factor β subunit) translocates into the nucleus and activates signaling components of RUNX (one of the runt-related transcription factor family member), leaving behind free cytoplasmic binding partner FLNA (Flaming A). They also show strong correlation between CBFb and regeneration of chrondocytes.
Stem cell therapy has uncounted potential for giving better life to patients with complex, chronic diseases. Johnson et al’s, discovery of a small molecule, KGN, with further research in animal and human population, could lead to the development of an effective stem cell based treatment of Osteoarthritis. A possibility of such a drug can be seen as a lifestyle changing drug in patients who have very limited options of treatments today.
Sources:
Johnson et al article: http://www.ncbi.nlm.nih.gov/pubmed/22491093
Arthritis information: http://orthopedics.about.com/cs/arthritis/a/arthritis.htm, h
http://www.cirm.ca.gov/node/2082
Stem cells: http://www.stemcellresources.org/pdf/uw_rm.pdf
http://stemcells.nih.gov/staticresources/info/scireport/PDFs/Regenerative_Medicine_2006.pdf
Kafienah et al article: http://www.ncbi.nlm.nih.gov/pubmed/17195220
Previous post in awesome capital on the paper by Johnson et. al. : http://www.awesomecapital.com/1/post/2012/04/novartis-anti-arthritis-compound-spurs-cartilage-growth-from-stem-cells.html
Information about cartilage repair : http://www.jointpain.md/Procedures/CartilageTransplant.aspx
Cartilage Supplement in iHealth directory:http://www.ihealthdirectory.com/cartilage-regeneration-supplements/
Information about modern cartilage repair treatments offered at Brigham and Women Hospital: http://www.brighamandwomens.org/Departments_and_Services/orthopedics/services/CartilageRepair/default.aspx
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Anamika and Ritu,
This is a HOT topic, great post and very important research finding are reported.
Please review the following and consider to add the new material from these source by using Edit. Then, please post on FB and connect to all LinkedIn Groups both of you belong to.
http://www.brighamandwomens.org/departments_and_services/orthopedics/services/accss/Default.aspx
http://www.awesomecapital.com/1/post/2012/04/novartis-anti-arthritis-compound-spurs-cartilage-growth-from-stem-cells.html
http://www.jointpain.md/Procedures/CartilageTransplant.aspx
Biological resurfacing of articular cartilage lesions is an exciting field. Advances in understanding the biology of articular cartilage in health and disease, and the development of new techniques in repair, regeneration, and replacement of articular cartilage have led to the application of new therapies. These therapies can be classified into reparative therapies and restorative therapies. In reparative therapies, tissue that can function as an articular surface but that is not histologically equivalent to hyaline articular cartilage is regenerated. In restorative therapies, mature hyaline cartilage is implanted into a chondral lesion. The most common clinically relevant cartilage resurfacing techniques presently in use include microfracture, autologous chondrocyte implantation (ACI), autologous osteochondral transfer (OATS or mosaicplasty), and osteochondral allograft transplantation. Although the indications for each technique differ, published clinical outcomes are generally similar
Dear Aviva:
Thank you for your suggestion. The links have been added as Sources in the article.
Was the process of how KGN was discovered covered in the Science article? Was it surrendipitously or was it directed as with high throughput screening for biological activity, etc?
Hello Joel:
In the Science paper they do cover how KGN was discovered. They used high throughput screening of 22,000 different structures heterocyclic drug like molecules. The authors report that only 100nM KGN responded positively among all the other candidates.
Anamika,
Thank you for the additions to original post and for addressing Joel’s comment which is one even myself wish to know.
[…] A possible light by Stem cell therapy in painful dark of Osteoarthritis” – Kartogenin, a small m… Author and Reporter: Anamika Sarkar, Ph.D and Ritu Saxena, Ph.D. […]
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette