Parathyroid Hormone Regulation of the Rat Collagenase-3 Promoter by Protein Kinase A-dependent Transactivation of Core Binding Factor α1

Selvamurugan, N.; Pulumati, Malini R.; Tyson, Darren R.; Partridge, Nicola C.

doi:10.1074/jbc.275.7.5037

Cited by 185 publications

(152 citation statements)

References 50 publications

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“…3B). The concentrations of the inhibitors or activators used in this study are in the ranges reported by us and others to selectively affect the relevant pathways (18,(47)(48)(49). We found no evidence of toxicity.…”

Section: Pth Stimulates Osteocalcin Gene Expression and Promotermentioning

confidence: 69%

Parathyroid Hormone Induction of the Osteocalcin Gene

Jiang

Franceschi

Boules

et al. 2004

Journal of Biological Chemistry

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Parathyroid hormone (PTH) is an important peptide hormone regulator of bone formation and osteoblast activity. However, its mechanism of action in bone cells is largely unknown. This study examined the effect of PTH on mouse osteocalcin gene expression in MC3T3-E1 preosteoblastic cells and primary cultures of bone marrow stromal cells. PTH increased the levels of osteocalcin mRNA 4 -5-fold in both cell types. PTH also stimulated transcriptional activity of a 1.3-kb fragment of the mouse osteocalcin gene 2 (mOG2) promoter. Inhibitor studies revealed a requirement for protein kinase A, protein kinase C, and mitogen-activated protein kinase pathways in the PTH response. Deletion of the mOG2 promoter sequence from ؊1316 to ؊116 caused no loss in PTH responsiveness whereas deletion from ؊116 to ؊34 completely prevented PTH stimulation. Interestingly, this promoter region does not contain the RUNX2 binding site shown to be necessary for PTH responsiveness in other systems. Nuclear extracts from PTH-treated MC3T3-E1 cells exhibited increased binding to OSE1, a previously described osteoblast-specific enhancer in the mOG2 promoter. Furthermore, mutation of OSE1 in DNA transfection assays established the requirement for this element in the PTH response. Collectively, these studies establish that actions of PTH on the osteocalcin gene are mediated by multiple signaling pathways and require OSE1 and associated nuclear proteins.Parathyroid hormone (PTH) 1 is a major regulator of calcium homeostasis. PTH has catabolic and anabolic effects on osteoblasts and bone in vitro and in vivo, which depend on the temporal pattern of administration; continuous administration decreases bone mass whereas intermittent administration increases bone mass (1-4). PTH functions through the PTH-1 receptor, a G protein-coupled receptor that is expressed in osteoblasts (5-7). Binding of PTH to its receptor activates multiple intracellular signaling pathways that involve cyclic cAMP, inositol phosphates, intracellular Ca 2ϩ , protein kinases A and C (2), and the extracellular signal-regulated kinase/ mitogen-activated protein kinase (MAPK) pathway (8, 9).Osteocalcin (OCN), a 5700-dalton ␥-carboxyglutamic acidcontaining noncollagenous protein, is a major component of the bone extracellular matrix. Although the functions of OCN are poorly understood, gene deletion studies suggest possible functions in bone remodeling (10). The expression of OCN is regulated by a number of calcitropic hormones and growth factors including 1,25-dihydroxy vitamin D 3 (11-13), glucocorticoids (14, 15), PTH (16), bone morphogenetic proteins (17), basic fibroblast growth factor 2 (18), tumor necrosis factor-␣ (19), and transforming growth factor ␤ (20). A number of transcription factors that bind to specific regions of the osteocalcin gene promoter have also been identified. These factors include AP-1 family members (21, 22), MSX-2/HOX 8.1 (23, 24), DLX-5 (25), CCAAT/enhancer binding proteins (26), and RUNX2 (27), the osteoblast-specific product of the Cbfa1 gene. These f...

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Section: Pth Stimulates Osteocalcin Gene Expression and Promotermentioning

confidence: 69%

Parathyroid Hormone Induction of the Osteocalcin Gene

Jiang

Franceschi

Boules

et al. 2004

Journal of Biological Chemistry

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“…(47) In addition, Ser22 phosphorylated by PKCd and Thr341 phosphorylated by PKA are required for, respectively, FGF2 and PTH-induced Runx2 activation and osteoblastic differentiation. (48,49) Contrarily, the phosphorylation of Ser369, 373, and 377 by GSK3b was shown to inhibit Runx2 transcriptional activity. (50) In summary, in this study we have provided evidence to support the negative role of JNK1 activated by BMP2 during osteoblastic differentiation.…”

Section: Discussionmentioning

confidence: 99%

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

Huang¹,

Lin²,

Chao³

et al. 2012

Journal of Bone and Mineral Research

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Runx2 plays a crucial role in osteoblastic differentiation, which can be upregulated by bone morphogenetic proteins 2 (BMP2). Mitogenactivated protein kinase (MAPK) cascades, such as extracellular signal-regulated kinase (ERK) and p38, have been reported to be activated by BMP2 to increase Runx2 activity. The role of cjun-N-terminal kinase (JNK), the other kinase of MAPK, in osteoblastic differentiation has not been well elucidated. In this study, we first showed that JNK1 is activated by BMP2 in multipotent C2C12 and preosteoblastic MC3T3-E1 cell lines. We then showed that early and late osteoblastic differentiation, represented by ALP expression and mineralization, respectively, are significantly enhanced by JNK1 loss-of-function, such as treatment of JNK inhibitor, knockdown of JNK1 and ectopic expression of a dominant negative JNK1 (DN-JNK1). Consistently, BMP2-induced osteoblastic differentiation is reduced by JNK1 gain-offunction, such as enforced expression of a constitutively active JNK1 (CA-JNK1). Most importantly, we showed that Runx2 is required for JNK1-mediated inhibition of osteoblastic differentiation, and identified Ser104 of Runx2 is the site phosphorylated by JNK1 upon BMP2 stimulation. Finally, we found that overexpression of the mutant Runx2 (Ser104Ala) stimulates osteoblastic differentiation of C2C12 and MC3T3-E1 cells to the extent similar to that achieved by overexpression of wild-type (WT) Runx2 plus JNK inhibitor treatment. Taken together, these data indicate that JNK1 negatively regulates BMP2-induced osteoblastic differentiation through phosphorylation of Runx2 at Ser104. In addition, unraveling these mechanisms may help to develop new strategies in enhancing osteoblastic differentiation and bone formation. ß

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“…Intermittent administration of PTH(1-34) has been shown to stimulate bone formation (21,22) and is used for treating osteoporosis (23)(24)(25). The function of PTH(1-34) on osteoblastlineage cells for bone formation is mediated through PTHR1, a heterotrimeric G protein-coupled receptor (26) that primarily mediates PTH signaling and then transmits it through protein kinase A (PKA) and PKC intracellular signaling pathways (27,28). The 1-34 amino acid fragments of both PTH and PTHrP contain the functional subdomains for PTHR1 signaling (29,30).…”

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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Parathyroid Hormone Regulation of the Rat Collagenase-3 Promoter by Protein Kinase A-dependent Transactivation of Core Binding Factor α1

Cited by 185 publications

References 50 publications

Parathyroid Hormone Induction of the Osteocalcin Gene

Parathyroid Hormone Induction of the Osteocalcin Gene

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

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

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