Talk:Musculoskeletal System - Bone Development
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Cite this page: Hill, M.A. (2024, May 19) Embryology Musculoskeletal System - Bone Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Musculoskeletal_System_-_Bone_Development |
2010
Sclerostin
J Osteoporos. 2010 Sep 29;2010:941419.
Silverman SL.
Cedars-Sinai, UCLA, OMC Clinical Research Center, 8641 Wilshire Boulevard, Suite 301, Beverly Hills, CA 90211, USA. Abstract The striking clinical benefits of intermittent parathyroid hormone in osteoporosis have begun a new era of skeletal anabolic agents. One potential new agent is monoclonal antibody to sclerostin, a potent inhibitor of osteoblastogenesis.
The Wnt signaling pathway demonstrates a complex network of proteins well known for their roles in embryogenesis but also involving normal physiologic processes of bone formation in response to loading and unloading [1]. The Wnt pathway involves a large network of proteins that can regulate the production of Wnt signaling molecules [2]. Several proteins that inhibit Wnt signaling [2] have been described. One such protein is sclerostin which binds low-density lipoprotein receptor-related protein (LRP) and inhibits Wnt signaling.
PMID: 20981340
http://www.ncbi.nlm.nih.gov/pubmed/20981340
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957275/
FGFs in endochondral skeletal development
J Cell Biochem. 2010 Aug 1;110(5):1046-57.
Degnin CR, Laederich MB, Horton WA. Shriners Hospital and Molecular & Medical Genetics and Cell & Developmental Biology, Oregon Health & Sciences University, Portland, Oregon 97239, USA.
Abstract The mammalian skeleton developments and grows through two complementary pathways: membranous ossification, which gives rise to the calvarial bones and distal clavicle, and endochondral ossification, which is responsible for the bones of the limbs, girdles, vertebrae, face and base of the skull and the medial clavicle. Fibroblast growth factors (FGFs) and their cognate FGF receptors (FGFRs) play important roles in regulating both pathways. However, the details of how FGF signals are initiated, propagated and modulated within the developing skeleton are only slowly emerging. This prospect will focus on the current understanding of these events during endochondral skeletal development with special attention given to concepts that have emerged in the past few years. Published 2010 Wiley-Liss, Inc.
PMID: 20564212
Control of Dkk-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees
Arthritis Rheum. 2010 May;62(5):1393-402.
Weng LH, Wang CJ, Ko JY, Sun YC, Wang FS.
Chang Gung Memorial Hospital-Kaohsiung Medical Center and Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan. Abstract OBJECTIVE: Perturbation of Wnt signaling components reportedly regulates chondrocyte fate and joint disorders. The Wnt inhibitor Dkk-1 mediates remodeling of various tissue types. We undertook this study to examine whether control of Dkk-1 expression prevents joint deterioration in osteoarthritic (OA) knees.
METHODS: Anterior cruciate ligament transection-and collagenase-induced OA in rat knees was treated with end-capped phosphorothioate Dkk-1 antisense oligonucleotide (Dkk-1-AS). Articular cartilage destruction, cartilage degradation markers, bone mineral density (BMD), and subchondral trabecular bone volume of injured knee joints were measured using Mankin scoring, enzyme-linked immunosorbent assay, dual x-ray absorptiometry, and histomorphometry. Dkk-1-responsive molecule expression and apoptotic cells in knee tissue were detected by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and TUNEL staining.
RESULTS: Up-regulated Dkk-1 expression was associated with increased Mankin score and with increased serum levels of cartilage oligomeric matrix protein and C-telopeptide of type II collagen (CTX-II) during OA development. Dkk-1-AS treatment alleviated OA-associated increases in Dkk-1 expression, Mankin score, cartilage fibrillation, and serum cartilage degradation markers. Dkk-1-AS also alleviated epiphyseal BMD loss and subchondral bone exposure associated with altered serum levels of osteocalcin and CTX-I. The treatment abrogated chondrocyte/osteoblast apoptosis and subchondral trabecular bone remodeling in OA. Dkk-1 knockdown increased levels of nuclear beta-catenin and phosphorylated Ser(473)-Akt but attenuated expression of inflammatory factors (Toll-like receptor 4 [TLR-4], TLR-9, interleukin-1beta, and tumor necrosis factor alpha), the apoptosis regulator Bax, matrix metalloproteinase 3, and RANKL in OA knee joints.
CONCLUSION: Interference with the cartilage- and bone-deleterious actions of Dkk-1 provides therapeutic potential for alleviating cartilage destruction and subchondral bone damage in OA knee joints.
PMID: 20131282
2007
Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF
Mol Cancer. 2007 Oct 30;6:71.
Fujita K, Janz S.
Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. fujitak@mail.nih.gov Abstract BACKGROUND: Enhanced osteoblast-dependent osteoclastogenesis due to inhibition of Wnt/beta-catenin signaling in bone morphogenic protein (BMP)-driven osteoprogenitors has been repeatedly implicated in the natural history of cancer-associated osteolytic lesions, but the mechanism of this bone loss is poorly understood.
METHODS: We examined the impact of secreted Wnt inhibitors from the Dickkopf (Dkk) family on pluripotent mesenchymal cells undergoing BMP2-induced osteoblastic differentiation.
RESULTS: We found that Dkk1 and -2 restored the Wnt3a-dependent reduction of alkaline phosphatase (ALP), Osterix and p53, indicating that mitigated Wnt/beta-catenin signaling promotes certain aspects of early osteoblastogenesis through the BMP-p53-Osterix-ALP axis. Dkk1 and -2 increased the expression of the osteoclast differentiation factors, receptor activator of NF-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF), upon stimulation with Wnt3a/1,25-dihydroxyvitamine D3 and Wnt3a/BMP2, respectively. The decoy receptor of RANKL, osteoprotegerin (OPG), was down regulated under the latter conditions. These findings indicated that Dkk1 and -2 facilitate osteoclastogenesis by enhancing RANKL/RANK and M-CSF/c-Fms interactions. Dkk4 weakly shared activities of Dkk-1 and -2, whereas Dkk3 was ineffective.
CONCLUSION: Our results suggest that inhibited Wnt/beta-catenin signaling in BMP2-induced osteoprogenitors in vivo promotes, on balance, the heightened formation of osteoclasts. Focally increased Dkk1 production by tumor cells in the bone may thus lead to focal bone loss.
PMID: 17971207
