Abnormal Compartmentalization of Cartilage Matrix Components in Mice Lacking Collagen X: Implications for Function

Kwan, Kin Ming; Pang, Michael K.M.; Zhou, Sheila X.; Cowan, S.K; Kong, Richard Yuen Chong; Pfordte, T; Olsen, Bjørn R.; Sillence, David; Tam, Patrick; Cheah, Kathryn S.E.

doi:10.1083/jcb.136.2.459

Cited by 185 publications

(160 citation statements)

References 41 publications

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“…S3), similar to that of C10cre::RLacZ mice. These data suggest that heterozygosity for Col10a1 does not cause the lineage transition and are consistent with previous reports showing that bone development is not affected in Col10a1 null mice (26,27).…”

Section: Significancesupporting

confidence: 81%

Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation

Yang

Tsang

Tang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

643

616

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According to current dogma, chondrocytes and osteoblasts are considered independent lineages derived from a common osteochondroprogenitor. In endochondral bone formation, chondrocytes undergo a series of differentiation steps to form the growth plate, and it generally is accepted that death is the ultimate fate of terminally differentiated hypertrophic chondrocytes (HCs). Osteoblasts, accompanying vascular invasion, lay down endochondral bone to replace cartilage. However, whether an HC can become an osteoblast and contribute to the full osteogenic lineage has been the subject of a century-long debate. Here we use a cell-specific tamoxifen-inducible genetic recombination approach to track the fate of murine HCs and show that they can survive the cartilageto-bone transition and become osteogenic cells in fetal and postnatal endochondral bones and persist into adulthood. This discovery of a chondrocyte-to-osteoblast lineage continuum revises concepts of the ontogeny of osteoblasts, with implications for the control of bone homeostasis and the interpretation of the underlying pathological bases of bone disorders.osteoblast ontogeny | chondrocyte lineage | bone repair I n vertebrates, the endochondral bones of the axial and appendicular skeleton (1) develop from mesenchymal progenitors that form condensations in the approximate shape of the future skeletal elements. These progenitors differentiate into chondrocytes, which proliferate, mature, and undergo hypertrophy, forming an avascular cartilaginous template surrounded by a perichondrium. The first osteoblasts differentiate from mesenchymal precursors in the perichondrium and produce a bone collar, which will become the future cortical bone (1). Blood vessels then invade through the bone collar into the hypertrophic cartilage, bringing in osteoblast progenitors from the perichondrium (2), which lay down bone matrix to form the primary ossification center (POC); the cartilage matrix is degraded; and the proximal and distal growth plates, comprising layers of differentiating chondrocytes and spongy/trabecular bone (the primary spongiosa), form (2). Thereafter, linear bone growth continues by endochondral ossification mediated by the growth plate, whereas osteoblasts in the perichondrium form cortical bone on the outer circumference.Chondrocytes and osteoblasts are regarded as separate lineages in development, being derived from common mesenchymal progenitors that express the transcription factors sex determining region Y (SRY)-box 9 (Sox9) and runt related transcription factor 2 (Runx2) (1). Lineage determination toward the chondrocyte or osteoblast fate is controlled by the relative expression of Sox9 and Runx2 (3-5) (Fig. 1A). Sox9 controls chondrocyte proliferation and their progression into hypertrophy (6). Collagen X is the most specific marker of hypertrophic chondrocytes (HCs), the Col10a1 gene being expressed only in prehypertrophic and hypertrophic chondrocytes in the growth plate (7). By contrast, Runx2 is essential for specifying the osteoblast lineage an...

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Section: Significancesupporting

confidence: 81%

Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation

Yang

Tsang

Tang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

643

616

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“…The growth plate defect of Grg5 null mice has many features shared with those of Col10a1 null or dominant negative collagen X transgenic mice (Jacenko et al, 1993;Kwan et al, 1997). These features include narrow zones of proliferative and hypertrophic chondrocytes in the growth plates, reduced height and density of trabecular bone regions underneath the growth plates, and enlarged resting zones.…”

Section: Discussionmentioning

confidence: 99%

Growth defect in Grg5 null mice is associated with reduced Ihh signaling in growth plates

Wang

Plotkina

et al. 2002

Developmental Dynamics

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Gene-targeted disruption of Grg5, a mouse homologue of Drosophila groucho (gro), results in postnatal growth retardation in mice. The growth defect, most striking in approximately half of the Grg5 null mice, occurs during the first 4 -5 weeks of age, but most mice recover retarded growth later. We used the nonlinear mixed-effects model to fit the growth data of wild-type, heterozygous, and Grg5 null mice. On the basis of preliminary evidence suggesting an interaction between Grg5 and the transcription factor Cbfa1/Runx2, critical for skeletal development, we further investigated the skeleton in the mice. A long bone growth plate defect was identified, which included shorter zones of proliferative and hypertrophic chondrocytes and decreased trabecular bone formation. This decreased trabecular bone formation is likely caused by a reduced recruitment of osteoblasts into the growth plate region of Grg5 null mice. Like the growth defect, the growth plate and trabecular bone abnormality improved as the mice grew older. The growth plate defect was associated with reduced Indian hedgehog expression and signaling. We suggest that Grg5, a transcriptional coregulator, modulates the activities of transcription factors, such as Cbfa1/Runx2 in vivo to affect Ihh expression and the function of long bone growth plates.

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“…Dedifferentiated chondrocytes are characterized by a remarkable increase in the expression of collagen type I and by a low level of proteoglycan production. Moreover, the expression of collagen type X also disfavors further implantation, because its expression precedes the onset of endochondral ossification (Kwan et al 1997). One solution is the use of growth factors, but the application of growth factors in clinics is limited due to the following reasons: 1) growth factors may induce the formation of osteophyte, resulting in degeneration of articular cartilage (Hsieh et al 2003); 2) they may lead to tumorigenesis (Waterfield et al 1983;Josephs et al 1984;Downward et al 1984); and 3) they are generally expensive.…”

Section: Introductionmentioning

confidence: 99%

Chondroprotective Effects of Taurine in Primary Cultures of Human Articular Chondrocytes

Liu

et al. 2015

Tohoku J. Exp. Med.

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Articular cartilage is characterized by the lack of blood vessels and has a poor self-healing potential. Limited cell numbers and dedifferentiation of chondrocytes when expanded in vitro are the major obstacles of autologous chondrocyte implantation. Autologous chondrocyte implantation is a cell-based treatment that can be used as a second-line measure to regenerate chondral or osteochondral defects in younger, active patients. There is an urgent need to find an effective chondrogenic protection agent alleviating or inhibiting chondrocyte dedifferentiation. In this study, we explored the effect of taurine (2-aminoethane sulfonic acid) on proliferation and phenotype maintenance of human articular chondrocytes by analyzing the cell proliferation, morphology, viability, and expression of cartilage specific mRNAs and proteins. Primary chondrocytes were isolated from human articular cartilage tissues. Results showed that taurine effectively promoted chondrocyte growth and enhanced accumulation of glycosaminoglycans and collagens in the conditioned media of chondrocytes. Moreover, taurine exposure caused significant increases in the relative expression levels of mRNAs for cartilage specific markers, including aggrecan, collagen type II and SOX9. Aggrecan is a cartilage-specific proteoglycan, and SOX9 is a chondrogenic transcription factor. In contrast, the mRNA expression of collagen type I, a marker for chondrocyte dedifferentiation, was significantly decreased in cells treated with taurine, indicating that taurine inhibits the chondrocyte dedifferentiation. This study reveals that taurine is effective in proliferation promotion and phenotype maintenance of chondrocytes. Thus, taurine may be a useful pro-chondrogenic agent for autologous chondrocyte implantation in the treatment of cartilage repair.

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Abnormal Compartmentalization of Cartilage Matrix Components in Mice Lacking Collagen X: Implications for Function

Cited by 185 publications

References 41 publications

Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation

Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation

Growth defect in Grg5 null mice is associated with reduced Ihh signaling in growth plates

Chondroprotective Effects of Taurine in Primary Cultures of Human Articular Chondrocytes

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