Four Distinct Chondrocyte Populations in the Fetal Bovine Growth Plate: Highest Expression Levels of PTH/PTHrP Receptor, Indian Hedgehog, and MMP-13 in Hypertrophic Chondrocytes and Their Suppression by PTH (1–34) and PTHrP (1–40)

Weisser, Jürgen; Riemer, Silvia; Schmidl, Martina; Suva, Larry J.; Pöschl, Ernst; Bräuer, Rolf; Mark, Klaus von der

doi:10.1006/excr.2002.5580

Cited by 54 publications

(54 citation statements)

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“…PTH was also reported to suppress expression of type X collagen and IHH, marker genes of hypertrophic chondrocytes, in growth plates (7). In contrast, a suppressive effect of PTH(1-84) on the repair of articular cartilage was found in a rabbit model of a full-thickness defect.…”

Section: Discussionmentioning

confidence: 99%

“…Meanwhile, a feedback loop regulating endochondral ossification in growth plates involves parathyroid hormone-related peptide (PTHrP), Indian hedgehog (IHH), and Bcl-2. PTHrP maintains the function of proliferating chondrocytes and inhibits chondrocyte differentiation toward hypertrophy (6,7). However, the role of PTHrP in articular chondrocyte functioning during OA-associated changes is not clear.…”

mentioning

confidence: 99%

“…It has been reported that parathyroid hormone receptor 1 (PTHR1) mediates the PTHrP signaling that serves to maintain the functioning of proliferating chondrocytes during endochondral ossification (7,8). Parathyroid hormone 1-34 (PTH ), a recombinant human parathyroid hormone analog, is currently used as an anabolic drug to treat osteoporosis.…”

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confidence: 99%

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Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats

Chang¹,

Chang²,

Hung³

et al. 2009

Arthritis & Rheumatism

100

120

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Objective. Parathyroid hormone 1-34 (PTH[1-34]), a parathyroid hormone analog, shares the same receptor, PTH receptor 1, with parathyroid hormone-related peptide (PTHrP). This study was undertaken to address the hypothesis that PTH(1-34) inhibits terminal differentiation of articular chondrocytes and in turn suppresses the progression of osteoarthritis (OA).Methods. We studied the effect of PTH(1-34) on human articular chondrocytes with azacytidine (azaC)-induced terminal differentiation in vitro and on papaininduced OA in the knee joints of rats. In the in vitro study, we measured the levels of messenger RNA for SOX9, aggrecan, type II collagen, type X collagen, alkaline phosphatase (AP), Indian hedgehog (IHH), Bcl-2, and Bax by real-time polymerase chain reaction, levels of glycosaminoglycan (GAG) by dimethylmethylene blue assay, and rate of apoptosis by TUNEL staining. In the in vivo study, we evaluated the histologic changes in GAG, type II collagen, type X collagen, and chondrocyte apoptosis in the articular cartilage of rat knees.Results. AzaC induced terminal differentiation of human chondrocytes, including down-regulation of aggrecan, type II collagen, and GAG and up-regulation of type X collagen, alkaline phosphatase, and IHH. Apoptosis was reversed by 3-10 days of treatment with 10 nM PTH(1-34). SOX9 expression was not changed by either azaC or PTH(1-34) treatment. Bcl-2 and Bax were up-regulated on day 10 and day 14, respectively, after azaC induction of terminal differentiation, but PTH(1-34) treatment did not reverse this effect. Furthermore, PTH(1-34) treatment reversed papaininduced OA changes (decreasing GAG and type II collagen, and increasing type X collagen and chondrocyte apoptosis) in the knee joints of rats.Conclusion. Our findings indicate that PTH(1-34) inhibits the terminal differentiation of human articular chondrocytes in vitro and inhibits progression of OA in rats in vivo, and may be used to treat OA.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats

Chang¹,

Chang²,

Hung³

et al. 2009

Arthritis & Rheumatism

100

120

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“…The PTHrP receptor is not expressed in undifferentiated MSCs and is up-regulated during chondrogenic differentiation of MSCs [4,5]. The N-terminal fragment PTHrP(1-40) is sufficient to suppress hypertrophy in chondrocytes [13]. Therefore, we hypothesise that PTHrP (1-40) can suppress hypertrophy in MSC chondrogenesis.…”

Section: Introductionmentioning

confidence: 96%

Effect of parathyroid hormone-related protein in an in vitro hypertrophy model for mesenchymal stem cell chondrogenesis

Mueller

Fischer²,

Zellner³

et al. 2013

International Orthopaedics (SICOT)

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Purpose Mesenchymal stem cells (MSCs) express markers of hypertrophic chondrocytes during chondrogenic differentiation. We tested the suitability of parathyroid hormonerelated protein (PTHrP), a regulator of chondrocyte hypertrophy in embryonic cartilage development, for the suppression of hypertrophy in an in vitro hypertrophy model of chondrifying MSCs. Methods Chondrogenesis was induced in human MSCs in pellet culture for two weeks and for an additional two weeks cultures were either maintained in standard chondrogenic medium or transferred to a hypertrophy-enhancing medium. PTHrP(1-40) was added to the medium throughout the culture period at concentrations from 1 to 1,000 pM. Pellets were harvested on days one, 14 and 28 for biochemical and histological analysis. Results Hypertrophic medium clearly enhanced the hypertrophic phenotype, with increased cell size, and strong alkaline phosphatase (ALP) and type X collagen staining. In chondrogenic medium, 1-100 pM PTHrP(1-40) did not inhibit chondrogenic differentiation, whereas 1,000 pM PTHrP(1-40) significantly reduced chondrogenesis. ALP activity was dose-dependently reduced by PTHrP(1-40) at 10-1,000 pM in chondrogenic conditions. Under hypertrophy-enhancing conditions, PTHrP(1-40) did not inhibit the induction of the hypertrophy. At the highest concentration (1,000 pM) in the hypertrophic group, aggregates were partially dedifferentiated and differentiated areas of these aggregates maintained their hypertrophic appearance. Conclusions PTHrP(1-40) treatment dose-dependently reduced ALP expression in MSC pellets cultured under standard chondrogenic conditions and is thus beneficial for the maintenance of the chondrogenic phenotype in this medium condition. When cultured under hypertrophy-enhancing conditions, PTHrP(1-40) could not diminish the induced enhancement of hypertrophy in the MSC pellets.

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“…The isolation of chondrocyte populations from cartilage of larger species, including bovine and chicken, has been achieved by using specific cell characteristics, such as different cell sedimentation rates, (5)(6)(7)(8) but the low recovery of purified cells renders this approach unsuitable for mouse cartilage. (9) Fluorescence-activated cell sorting (FACS) combined with immunomagnetic cell separation appears as an ideal alternative method to sort viable cell populations (9,10) but could not be applied to growth plate chondrocytes owing to the lack of suitable cell surface markers and corresponding antibodies.…”

Section: Introductionmentioning

confidence: 99%

Sorting of growth plate chondrocytes allows the isolation and characterization of cells of a defined differentiation status

Belluoccio¹,

Etich²,

Rosenbaum³

et al. 2010

Journal of Bone and Mineral Research

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Axial growth of long bones occurs through a coordinated process of growth plate chondrocyte proliferation and differentiation. This maturation of chondrocytes is reflected in a zonal change in gene expression and cell morphology from resting to proliferative, prehypertrophic, and hypertrophic chondrocytes of the growth plate followed by ossification. A major experimental limitation in understanding growth plate biology and pathophysiology is the lack of a robust technique to isolate cells from the different zones, particularly from small animals. Here, we report on a new strategy for separating distinct chondrocyte populations from mouse growth plates. By transcriptome profiling of microdissected zones of growth plates, we identified novel, zone-specific cell surface markers and used these for flow cytometry and immunomagnetic cell separation to quantify, enrich, and characterize chondrocytes populations with respect to their differentiation status. This approach provides a novel platform to study cartilage development and characterize mouse growth plate chondrocytes to reveal unique cellular phenotypes of the distinct subpopulations within the growth plate. ß

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Four Distinct Chondrocyte Populations in the Fetal Bovine Growth Plate: Highest Expression Levels of PTH/PTHrP Receptor, Indian Hedgehog, and MMP-13 in Hypertrophic Chondrocytes and Their Suppression by PTH (1–34) and PTHrP (1–40)

Cited by 54 publications

References 58 publications

Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats

Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats

Effect of parathyroid hormone-related protein in an in vitro hypertrophy model for mesenchymal stem cell chondrogenesis

Sorting of growth plate chondrocytes allows the isolation and characterization of cells of a defined differentiation status

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