Parathyroid Hormone-(1–34) Enhances Aggrecan Synthesis via an Insulin-like Growth Factor-I Pathway

Yu, Xiaopeng; Frolik, Charles A.; Chandrasekhar, Srinivasan

doi:10.1074/jbc.274.33.23249

Cited by 31 publications

(21 citation statements)

References 32 publications

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“…This, as well as developmental and differentiation expression dependent pattern, may be the cause of the distinct expression pattern observed in both models. This is supported by observations in rat costal chondrocytes in which PTHrP either induced, slightly repressed or had no effect on Agc mRNA expression depending on the gestational age of the cells [41]. …”

Section: Discussionsupporting

confidence: 68%

Novel Late Response Genes of PTHrP in Chondrocytes

Hoogendam¹,

Farih-Sips²,

Beek³

et al. 2006

Horm Res Paediatr

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To gain more insight into the downstream effectors of parathyroid hormone (PTH) related peptide (PTHrP) signaling in chondrocytes, we performed microarray analysis to identify late PTHrP response genes using the chondrogenic ATDC5 cell line and studied their response in the osteoblastic KS483 cell line and explanted metatarsals. At day 8 of micromass culture, ATDC5 cells have pre-hypertrophic-like characteristics and at this time point the cells were stimulated with PTHrP for 24 and 72 h and RNA was isolated. PTHrP treatment inhibited outgrowth of cartilage matrix and decreased the expression of Col10a1 mRNA, which is in line with the inhibitory effects of PTHrP on chondrocyte differentiation. Using cDNA microarray analysis, a list of 9 genes (p< 10^–3) was generated, including 3 upregulated (IGFBP4, Csrp2, and Ecm1) and 6 downregulated (Col9a1, Col2a1, Agc, Hmgn2, Calm1, and Mxd4) response genes. Four out of 9 genes are novel PTHrP response genes and 2 out of 9 have not yet been identified in cartilage. Four out of 9 genes are components of the extra-cellular matrix and the remaining genes are involved in signal transduction and transcription regulation. The response to PTHrP was validated by quantitative PCR, using the same RNA samples as labeled in the microarray experiments and RNA samples isolated from a new experiment. In addition, we examined whether these genes also reacted to PTHrP in other PTHrP responsive models, like KS483 osteoblasts and explanted metatarsals. The expression of late PTHrP response genes varied between ATDC5 chondrocytes, KS483 osteoblasts and metatarsals, suggesting that the expression of late response genes is dependent on the cellular context of the PTHrP responsive cells.

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Section: Discussionsupporting

confidence: 68%

Novel Late Response Genes of PTHrP in Chondrocytes

Hoogendam¹,

Farih-Sips²,

Beek³

et al. 2006

Horm Res Paediatr

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“…Previous data suggest that, because they share the same receptor (PTHR1), PTH(1-34) has similar effects as PTHrP in enhancing aggrecan synthesis in rib cage chondrocytes in developing rat embryos (41). PTH was also reported to suppress expression of type X collagen and IHH, marker genes of hypertrophic chondrocytes, in growth plates (7).…”

Section: Discussionmentioning

confidence: 99%

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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“…There are few reports of their use in chondrocyte cultures. Two are studies of parathyroid hormone and parathyroid related peptide functions [Harvey et al, 1999;Wood et al, 1990], and there is one study of the use of blocking antibodies to evaluate the role of integrins in the micromass culture system [Shakibaei and Merker, 1999].…”

Section: Discussionmentioning

confidence: 99%

Type I collagen influences cartilage calcification: An immunoblocking study in differentiating chick limb-bud mesenchymal cell cultures

et al. 2000

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Chick limb-bud mesenchymal cells, plated in high-density micro-mass culture, differentiate and form a matrix resembling chick epiphyseal cartilage. In the presence of 4 mM inorganic phosphate or 2.5 mM beta-glycerophosphate mineral deposits upon this matrix forming a mineralized tissue that, based on electron microscopy, x-ray diffraction and Fourier Transform Infrared microspectoscopy, is like that of chick calcified cartilage. In this culture system the initial mineral deposits are found on the periphery of the chondrocyte nodules. During differentiation of the cells in the high-density micro-mass cultures there is a switch from expression of type I collagen to type II, and then to type X collagen. However, type I collagen persists in the matrix. Because there is some debate about whether type I collagen influences cartilage calcification, an immunoblocking technique was used to determine the importance of type I collagen on the mineralization process in this system. Studies using nonspecific goat anti-chick IgG demonstrated that 1-100 ng/ml antibody added with the media after the cartilage nodules had developed (day 7) had no effect on the accumulation of mineral in the cultures. Nonspecific antibody added before day 7 blocked development of the cultures. Parallel solution based cell-free studies showed that IgG did not have a strong affinity for apatite crystals, and had no significant effect on apatite crystal growth. Type I collagen antibodies (1-200 ng/ml) added to cultures one time on day 9 (before mineralization started), or on day 11 (at the start of mineralization), slightly inhibited the accumulation of mineral. There was a statistically significant decrease in mineral accretion with 100 or 200 ng/ml collagen antibody addition continuously after these times. Fab' fragments of nonspecific and type I collagen antibodies had effects parallel to those of the intact antibodies, indicating that the decreased mineralization was not attributable to the presence of the larger, bulkier antibodies. The altered accumulation of mineral was not associated with cell death in the presence of antibody (demonstrated by fluorescent labeling of DNA) or with increased apoptosis (TUNEL-stain). In the immunoblocked cultures, EM analysis demonstrated that mineral continued to deposit on collagen fibrils, but there appeared to be fewer deposits. The data demonstrate that type I collagen is important for the mineralization of these cultures.

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Parathyroid Hormone-(1–34) Enhances Aggrecan Synthesis via an Insulin-like Growth Factor-I Pathway

Cited by 31 publications

References 32 publications

Novel Late Response Genes of PTHrP in Chondrocytes

Novel Late Response Genes of PTHrP in Chondrocytes

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

Type I collagen influences cartilage calcification: An immunoblocking study in differentiating chick limb-bud mesenchymal cell cultures

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