Talk:Musculoskeletal System - Bone Development

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On this website the Discussion Tab or "talk pages" for a topic has been used for several purposes: References - recent and historic that relates to the topic Additional topic information - currently prepared in draft format Links - to related webpages Topic page - an edit history as used on other Wiki sites Lecture/Practical - student feedback Student Projects - online project discussions. Links: Pubmed Most Recent | Reference Tutorial | Journal Searches Glossary Links Glossary: A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers | Symbols | Term Link Cite this page: Hill, M.A. (2024, May 8) Embryology Musculoskeletal System - Bone Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Musculoskeletal_System_-_Bone_Development

Zone	Acronym	Cells	Properties
Resting or Germinal	RZ	small uniform compactly located chondrocytes	rich in lipid and cytoplasmic vacuoles low rates of chondrocytes replication, proteoglycan and collagen type IIB synthesis.
Proliferative	PZ	chondrocyte are tightly bound in columns parallel to the axis of the length of the bone	they can proliferate and differentiate.
Hypertrophic	HZ	upper zone of maturation and the lower zone of degeneration	layer where blood vessels invade, along with chondroclasts that degrade and remodel the cartilage extracellular matrix
Calcification	CZ	Osteoblast precursor cells that adhere to the remnants of the cartilage ECM	form bone tissue in primary ossification centres to assemble the provisional calcification zone

Old Histology Slides: developing Vertebra | Vertebra medium

Endochondral ossification slides: Developing bone | Bone, Developing (LS, Femur) Cat H&E

10 Most Recent Papers

Note - This sub-heading shows an automated computer PubMed search using the listed sub-heading term. References appear in this list based upon the date of the actual page viewing. Therefore the list of references do not reflect any editorial selection of material based on content or relevance. In comparison, references listed on the content page and discussion page (under the publication year sub-headings) do include editorial selection based upon relevance and availability. (More? Pubmed Most Recent)

Bone Development

<pubmed limit=5>Bone Development</pubmed>

Bone Embryology

<pubmed limit=5>Bone Embryology</pubmed>

2014

Vascularization of primary and secondary ossification centres in the human growth plate

BMC Dev Biol. 2014 Aug 28;14(1):36. [Epub ahead of print]

Walzer SM, Cetin E, Grübl-Barabas R, Sulzbacher I, Rueger B, Girsch W, Toegel S, Windhager R, Fischer MB.

Abstract

BackgroundThe switch from cartilage template to bone during endochondral ossification of the growth plate requires a dynamic and close interaction between cartilage and the developing vasculature. Vascular invasion of the primarily avascular hypertrophic chondrocyte zone brings chondroclasts, osteoblast- and endothelial precursor cells into future centres of ossification.Vascularization of human growth plates of polydactylic digits was studied by immunohistochemistry, confocal-laser-scanning-microscopy and RT-qPCR using markers specific for endothelial cells CD34 and CD31, smooth muscle cells ¿-SMA, endothelial progenitor cells CD133, CXCR4, VEGFR-2 and mesenchymal progenitor cells CD90 and CD105. In addition, morphometric analysis was performed to quantify RUNX2+ and DLX5+ hypertrophic chondrocytes, RANK+ chondro- and osteoclasts, and CD133+ progenitors in different zones of the growth plate.ResultsNew vessels in ossification centres were formed by sprouting of CD34+ endothelial cells that did not co-express the mature endothelial cell marker CD31. These immature vessels in the growth plate showed no abluminal coverage with ¿-SMA+ smooth muscle cells, but in their close proximity single CD133+ precursor cells were found that did not express VEGFR-2, a marker for endothelial lineage commitment. In periosteum and in the perichondrial groove of Ranvier that harboured CD90+/CD105+ chondro-progenitors, in contrast, mature vessels were found stabilized by ¿-SMA+ smooth muscle cells.ConclusionVascularization of ossification centres of the growth plate was mediated by sprouting of capillaries coming from the bone collar or by intussusception rather than by de-novo vessel formation involving endothelial progenitor cells. Vascular invasion of the joint anlage was temporally delayed compared to the surrounding joint tissue.

PMID 25164565

http://www.biomedcentral.com/1471-213X/14/36/abstract

Histogenesis of Japanese quail bone and cartilage tissues at the final stages of embryonic development in microgravity

Aviakosm Ekolog Med. 2013 Nov-Dec;47(6):24-8.

[Article in Russian] Komissarova DV, Dadasheva OA, Gurieva TS, Sychev VN. Abstract The article reports the results of comparative histological studies of skeleton development in 14- and 16-day Japanese quail embryos grown in space flight and in the 1-g gravity. The investigation revealed retardation of cartilage replacement by bone in the femur and tibia in space embryos as compared with their controls. Perichondral ossification metaphysis was reached by day 14 both in the space and control embryos. Destruction of cartilaginous diaphysis advanced onto the proximal and distal parts including the periphery. Tibia and femur cartilaginous cores in space embryos were destructed worse than in the controls in consequence of insufficient minerals supply. Perichondral ossification in the 16-day space and control embryos was alike close to completion spreading as far as the epiphysis. Long bones metaphysis was abundant in monomorphic cells as a growth bank existing during and 7 days post hatching. However, absence, in contrast to the controls, of osteogensis sites in long bones epiphysis, suggested retardation of chondrocytes calcification in these areas, as well as of ossification in space embryos. PMID 24660239

2012

A unified anatomy ontology of the vertebrate skeletal system

PLoS One. 2012;7(12):e51070. doi: 10.1371/journal.pone.0051070. Epub 2012 Dec 10.

Dahdul WM, Balhoff JP, Blackburn DC, Diehl AD, Haendel MA, Hall BK, Lapp H, Lundberg JG, Mungall CJ, Ringwald M, Segerdell E, Van Slyke CE, Vickaryous MK, Westerfield M, Mabee PM. Source Department of Biology, University of South Dakota, Vermillion, South Dakota, United States of America ; National Evolutionary Synthesis Center, Durham, North Carolina, United States of America.

Abstract

The skeleton is of fundamental importance in research in comparative vertebrate morphology, paleontology, biomechanics, developmental biology, and systematics. Motivated by research questions that require computational access to and comparative reasoning across the diverse skeletal phenotypes of vertebrates, we developed a module of anatomical concepts for the skeletal system, the Vertebrate Skeletal Anatomy Ontology (VSAO), to accommodate and unify the existing skeletal terminologies for the species-specific (mouse, the frog Xenopus, zebrafish) and multispecies (teleost, amphibian) vertebrate anatomy ontologies. Previous differences between these terminologies prevented even simple queries across databases pertaining to vertebrate morphology. This module of upper-level and specific skeletal terms currently includes 223 defined terms and 179 synonyms that integrate skeletal cells, tissues, biological processes, organs (skeletal elements such as bones and cartilages), and subdivisions of the skeletal system. The VSAO is designed to integrate with other ontologies, including the Common Anatomy Reference Ontology (CARO), Gene Ontology (GO), Uberon, and Cell Ontology (CL), and it is freely available to the community to be updated with additional terms required for research. Its structure accommodates anatomical variation among vertebrate species in development, structure, and composition. Annotation of diverse vertebrate phenotypes with this ontology will enable novel inquiries across the full spectrum of phenotypic diversity.

PMID 23251424

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0051070

Wnt-mediated reciprocal regulation between cartilage and bone development during endochondral ossification

Bone. 2012 Dec 26. pii: S8756-3282(12)01434-2. doi: 10.1016/j.bone.2012.12.016. [Epub ahead of print]

Lu C, Wan Y, Cao J, Zhu X, Yu J, Zhou R, Yao Y, Zhang L, Zhao H, Li H, Zhao J, He L, Ma G, Yang X, Yao Z, Guo X. Source Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240, China.

Abstract

The role of Wnt signaling is extensively studied in skeletal development and postnatal bone remodeling, mostly based on the genetic approaches of β-catenin manipulation. However, given their independent function, a requirement for β-catenin is not the same as that for Wnt. Here, we investigated the effect of Wnt proteins in both tissues through generating cartilage- or bone-specific Wls null mice, respectively. Depletion of Wls by Col2-Cre, which would block Wnt secretion in the chondrocytes and perichondrium, delayed chondrocyte hypertrophy in the growth plate and impaired perichondrial osteogenesis. Loss of Wls in chondrocytes also disturbed the proliferating chondrocyte morphology and division orientation, which was similar to the defect observed in Wnt5a null mice. On the other hand, inactivation of Wls in osteoblasts by Col1-Cre resulted in a shorter hypertrophic zone and an increase of TRAP positive cell number in the chondro-osseous junction of growth plate, coupled with a decrease in bone mass. Taken together, our studies reveal that Wnt proteins not only modulate differentiation and cellular communication within populations of chondrocytes, but also mediate the cross regulation between the chondrocytes and osteoblasts in growth plate. Copyright © 2012. Published by Elsevier Inc.

PMID 23274346

2011

Role of GSK-3β in the Osteogenic Differentiation of Palatal Mesenchyme

PLoS One. 2011;6(10):e25847. Epub 2011 Oct 14.

Nelson ER, Levi B, Sorkin M, James AW, Liu KJ, Quarto N, Longaker MT. Source Hagey Laboratory for Pediatric Regenerative Medicine, Plastic and Reconstructive Surgery Division, Department of Surgery, Stanford University School of Medicine, Stanford, California, United States of America.

Abstract

INTRODUCTION: The function of Glycogen Synthase Kinases 3β (GSK-3β) has previously been shown to be necessary for normal secondary palate development. Using GSK-3ß null mouse embryos, we examine the potential coordinate roles of Wnt and Hedgehog signaling on palatal ossification.

METHODS: Palates were harvested from GSK-3β, embryonic days 15.0-18.5 (e15.0-e18.5), and e15.5 Indian Hedgehog (Ihh) null embryos, and their wild-type littermates. The phenotype of GSK-3β null embryos was analyzed with skeletal whole mount and pentachrome stains. Spatiotemporal regulation of osteogenic gene expression, in addition to Wnt and Hedgehog signaling activity, were examined in vivo on GSK-3β and Ihh +/+ and -/- e15.5 embryos using in situ hybridization and immunohistochemistry. To corroborate these results, expression of the same molecular targets were assessed by qRT-PCR of e15.5 palates, or e13.5 palate cultures treated with both Wnt and Hedgehog agonists and anatagonists.

RESULTS: GSK-3β null embryos displayed a 48 percent decrease (*p<0.05) in palatine bone formation compared to wild-type littermates. GSK-3β null embryos also exhibited decreased osteogenic gene expression that was associated with increased Wnt and decreased Hedgehog signaling. e13.5 palate culture studies demonstrated that Wnt signaling negatively regulates both osteogenic gene expression and Hedgehog signaling activity, while inhibition of Wnt signaling augments both osteogenic gene expression and Hedgehog signaling activity. In addition, no differences in Wnt signaling activity were noted in Ihh null embryos, suggesting that canonical Wnt may be upstream of Hedgehog in secondary palate development. Lastly, we found that GSK-3β -/- palate cultures were "rescued" with the Wnt inhibitor, Dkk-1.

CONCLUSIONS: Here, we identify a critical role for GSK-3β in palatogenesis through its direct regulation of canonical Wnt signaling. These findings shed light on critical developmental pathways involved in palatogenesis and may lead to novel molecular targets to prevent cleft palate formation.

PMID 22022457 [PubMed - in process] PMCID: PMC3194817

2010

Developing bones are differentially affected by compromised skeletal muscle formation

Bone. 2010 May;46(5):1275-85. Epub 2009 Nov 27.

Nowlan NC, Bourdon C, Dumas G, Tajbakhsh S, Prendergast PJ, Murphy P.

Department of Zoology, School of Natural Sciences, Trinity College Dublin, Ireland. Abstract Mechanical forces are essential for normal adult bone function and repair, but the impact of prenatal muscle contractions on bone development remains to be explored in depth in mammalian model systems. In this study, we analyze skeletogenesis in two 'muscleless' mouse mutant models in which the formation of skeletal muscle development is disrupted; Myf5(nlacZ/nlacZ):MyoD(-/-) and Pax3(Sp/Sp) (Splotch). Ossification centers were found to be differentially affected in the muscleless limbs, with significant decreases in bone formation in the scapula, humerus, ulna and femur, but not in the tibia. In the scapula and humerus, the morphologies of ossification centers were abnormal in muscleless limbs. Histology of the humerus revealed a decreased extent of the hypertrophic zone in mutant limbs but no change in the shape of this region. The elbow joint was also found to be clearly affected with a dramatic reduction in the joint line, while no abnormalities were evident in the knee. The humeral deltoid tuberosity was significantly reduced in size in the Myf5(nlacZ/nlacZ):MyoD(-/-) mutants while a change in shape but not in size was found in the humeral tuberosities of the Pax3(Sp/Sp) mutants. We also examined skeletal development in a 'reduced muscle' model, the Myf5(nlacZ/+):MyoD(-/-) mutant, in which skeletal muscle forms but with reduced muscle mass. The reduced muscle phenotype appeared to have an intermediate effect on skeletal development, with reduced bone formation in the scapula and humerus compared to controls, but not in other rudiments. In summary, we have demonstrated that skeletal development is differentially affected by the lack of skeletal muscle, with certain rudiments and joints being more severely affected than others. These findings indicate that the response of skeletal progenitor cells to biophysical stimuli may depend upon their location in the embryonic limb, implying a complex interaction between mechanical forces and location-specific regulatory factors affecting bone and joint development.

Copyright (c) 2009 Elsevier Inc. All rights reserved.

PMID: 19948261 http://www.ncbi.nlm.nih.gov/pubmed/19948261

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

2009

Osteogenesis imperfecta: questions and answers

Curr Opin Pediatr. 2009 Dec;21(6):709-16.

Shapiro JR, Sponsellor PD.

Department Physical Medicine and Rehabilitation, Johns Hopkins University, Kennedy Krieger Institute, Baltimore, Maryland 21205, USA. shapiroj@KennedyKrieger.org Abstract PURPOSE OF REVIEW: Considerable attention has recently been focused on the pathogenesis, diagnosis and treatment of osteogenesis imperfecta. Two new genes have been defined in patients with recessive severe or lethal osteogenesis imperfecta types. Diagnostic concerns involve testing procedures, either skin biopsies or DNA analysis. Bisphosphonates have been accepted as 'standard of care' for children with osteogenesis imperfecta. However, questions remain as to the selection of patients for treatment, effectiveness in fracture prevention, which bisphosphonates should be used and the duration of treatment. Orthopedic intervention occurs on several levels: including the immediate treatment of fractures, the treatment of scoliosis and the use of intramedullary rods.

RECENT FINDINGS: The discovery of mutations involving CRTAP and LEPRE1 genes in severe/lethal and recessively inherited osteogenesis imperfecta has provided partial answers to questions about 'other' osteogenesis imperfecta genes in patients with an osteogenesis imperfecta phenotype but no COL1A1 and COL1A2 mutations. Current experience suggests that DNA analysis is a better test for diagnosis as compared with dermal biopsy. There are no standardized guidelines for initiating bisphosphonate treatment in children. Recent data suggest either intravenous or oral bisphosphonates are effective, but differences exist between different bisphosphonates. Two recent reports document the paucity of evidence-based data regarding the effectiveness of bisphosphonate treatment in fracture prevention.

SUMMARY: This report will update the medical and orthopedic approaches to care for children with osteogenesis imperfecta.

PMID: 19907330

http://www.ncbi.nlm.nih.gov/pubmed/19907330

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

Adult Bones Table

Axial Skeleton	Vertebral column	26
	Skull	22
	Hyoid bone	1
	Ribs and sternum	25
		—	74
Appendicular Skeleton	Upper extremities	64
	Lower extremities	62
		—	126
Auditory ossicles			6
			—
	Total		206