Bcl-2 Lies Downstream of Parathyroid Hormone–related Peptide in a Signaling Pathway That Regulates Chondrocyte Maturation during Skeletal Development

Amling, Michael; Neff, Lynn; Tanaka, Sakae; Inoue, Daisuke; Kuida, Keisuke; Weir, Eleanor C.; Philbrick, William M.; Broadus, Arthur E.; Baron, Roland

doi:10.1083/jcb.136.1.205

Cited by 299 publications

(242 citation statements)

References 46 publications

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“…4B), which is partly explained by the expansion of the hypertrophic layer of chondrocytes. Amling et al (14) found that Bcl2 expression is increased in late proliferative and prehypertrophic chondrocytes in transgenic mice overexpressing PTHrP in chondrocytes, but we found no change in Bcl2 mRNA levels in the growth plates of Coll2-CreER T :PPR fl/fl mice after administration of Tam. We focused on the BH3-only protein Bad because Bad is regulated by PKA, and therefore is a candidate regulator of apoptosis downstream of activation of the PPR.…”

Section: Discussioncontrasting

confidence: 44%

Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life

Hanabusa

Chagin

Kobayashi

et al. 2010

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

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Parathyroid hormone (PTH)-related protein (PTHrP), regulated by Indian hedgehog and acting through the PTH/PTHrP receptor (PPR), is crucial for normal cartilage development. These observations suggest a possible role of PPR signaling in the postnatal growth plate; however, the role of PPR signaling in postnatal chondrocytes is unknown. In this study, we have generated tamoxifen-inducible and cartilage-specific PPR KO mice to evaluate the physiological role of PPR signaling in postnatal chondrocytes. We found that inactivation of the PPR in chondrocytes postnatally leads to accelerated differentiation of chondrocytes, followed by disappearance of the growth plate. We also observed an increase of TUNEL-positive cells and activities of caspase-3 and caspase-9 in the growth plate, along with a decrease in phosphorylation of Bad at Ser155 in postnatal PPR KO mice. Administration of a lowphosphate diet, which prevents apoptosis of chondrocytes, prevented the disappearance of the growth plate. Taken together, these observations suggest that the major consequences of PPR activation are similar in both the fetal and postnatal growth plates. Moreover, chondrocyte apoptosis through the activation of a mitochondrial pathway may be involved in the process of premature disappearance of the growth plate by postnatal inactivation of the PPR in chondrocytes.

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Section: Discussioncontrasting

confidence: 44%

Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life

Hanabusa

Chagin

Kobayashi

et al. 2010

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

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“…Previous transgenic experiments have shown that Bcl-2 is a component of the PTH signaling pathway (11). We show here that the Bcl-2 level is regulated by the p38 MAPK activity.…”

Section: P38 Mapk Mediates Pth-regulated Chondrocyte Differentiationmentioning

confidence: 48%

“…elevating intracellular cAMP, thereby activating cAMP-dependent protein kinase A (PKA) or activating phospholipase C that results in an increase in intracellular free calcium and activation of protein kinase C (PKC) (10). It has also been shown that Bcl-2, an anti-apoptosis molecule, is also involved in the PTH/PTHrP signaling pathway in chondrocytes (11). In this study, we will determine the involvement of PKA and PKC pathways in transducing PTH/ PTHrP signals to regulate chondrocyte differentiation.…”

mentioning

confidence: 99%

Mitogen-activated Protein Kinase p38 Mediates Regulation of Chondrocyte Differentiation by Parathyroid Hormone

Zhen¹,

Wei²,

Wu³

et al. 2001

Journal of Biological Chemistry

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Parathyroid hormone (PTH) and its related peptide regulate endochondral ossification by inhibiting chondrocyte differentiation toward hypertrophy. However, the intracellular pathway for transducing PTH/PTH-related peptide signals in chondrocytes remains unclear. Here, we show that this pathway is mediated by mitogen-activated protein kinase (MAPK) p38. Incubation of hypertrophic chondrocytes with PTH (1-34) induces an inhibition of p38 kinase activity in a time-and dose-dependent manner. Inhibition of protein kinase C prevents PTH-induced p38 MAPK inhibition, whereas inhibition of protein kinase A has no effect. Thus, protein kinase C, but not protein kinase A, is required for the inhibition of p38 MAPK by PTH. Treatment of hypertrophic chondrocytes by PTH or by p38 MAPK inhibitor SB203580 up-regulates Bcl-2, suggesting that Bcl-2 lies downstream of p38 MAPK in the PTH signaling pathway. Inhibition of p38 MAPK in hypertrophic chondrocytes by either PTH, SB303580, or both together leads to a decrease of hypertrophic marker type X collagen mRNA and an increase of the expression of prehypertrophic marker cartilage matrix protein. Therefore, inhibition of p38 converts a hypertrophic cell phenotype to a prehypertrophic one, thereby preventing precocious chondrocyte hypertrophy. Taken together, these data suggest a major role for p38 MAPK in transmitting PTH signals to regulate chondrocyte differentiation.During endochondral ossification, chondrocytes undergo a differentiation process including proliferation, maturation, hypertrophy, and apoptosis (1). Cells from these different stages of differentiation synthesize specific molecules, for example, type X collagen is synthesized specifically by hypertrophic chondrocytes (2, 3), whereas cartilage matrix protein (CMP) 1 / matrilin-1, is a marker of prehypertrophic chondrocytes (1). Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) are major regulators of the chondrocyte differentiation process. PTH and PTHrP both bind to PTH receptors, which belong to G protein-coupled receptors (4). In a growth plate, PTH receptors are expressed at specific stages during chondrocyte differentiation, with the highest level at the prehypertrophic to hypertrophic transition (5). This suggests that PTH receptors may be important for the regulation of chondrocyte differentiation from the prehypertrophic state to the hypertrophic state. Indeed, overexpression of PTHrP or its constitutively active receptor in growth plates of transgenic mice delays endochondral bone formation (6), whereas mice with ablation of the PTH/PTHrP receptor gene develop skeletal dysplasia because of accelerated chondrocyte hypertrophy (7-9). Thus, the PTH/PTHrP receptor plays a fundamental role in the control of endochondral bone formation by transducing signals inhibiting chondrocyte hypertrophy. However, the intracellular signaling mechanism for PTH/PTHrP to regulate chondrocyte differentiation remains unknown.The PTH/PTHrP receptor may exert its biological action via at least two signaling p...

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“…These results suggested that Sox9 controls chondrocyte differentiation via PTHrP. PTHrP is known to play an important role in the regulation of proliferation, maturation, and apoptosis processes in chondrocytes (Weir et al, 1996;Amling et al, 1997;Zerega et al, 1999;Beier et al, 2001;Yamanaka et al, 2003). Furthermore, previous genetic studies have suggested an inhibitory role for Sox9 in the maturation of chondrocytes (Akiyama et al, 2004).…”

Section: Sox9 Family Induces Pthrp Expression In Chondrocytesmentioning

confidence: 67%

Sox9 Family Members Negatively Regulate Maturation and Calcification of Chondrocytes through Up-Regulation of Parathyroid Hormone–related Protein

Amano

Hata²,

Sugita³

et al. 2009

MBoC

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Sox9 is a transcription factor that plays an essential role in chondrogenesis and has been proposed to inhibit the late stages of endochondral ossification. However, the molecular mechanisms underlying the regulation of chondrocyte maturation and calcification by Sox9 remain unknown. In this study, we attempted to clarify roles of Sox9 in the late stages of chondrocyte differentiation. We found that overexpression of Sox9 alone or Sox9 together with Sox5 and Sox6 (Sox5/6/9) inhibited the maturation and calcification of murine primary chondrocytes and up-regulated parathyroid hormone-related protein (PTHrP) expression in primary chondrocytes and the mesenchymal cell line C3H10T1/2. Sox5/6/9 stimulated the early stages of chondrocyte proliferation and development. In contrast, Sox5/6/9 inhibited maturation and calcification of chondrocytes in organ culture. The inhibitory effects of Sox5/6/9 were rescued by treating with anti-PTHrP antibody. Moreover, Sox5/6/9 bound to the promoter region of the PTHrP gene and up-regulated PTHrP gene promoter activity. Interestingly, we also found that the Sox9 family members functionally collaborated with Ihh/Gli2 signaling to regulate PTHrP expression and chondrocyte differentiation. Our results provide novel evidence that Sox9 family members mediate endochondral ossification by up-regulating PTHrP expression in association with Ihh/Gli2 signaling.

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Bcl-2 Lies Downstream of Parathyroid Hormone–related Peptide in a Signaling Pathway That Regulates Chondrocyte Maturation during Skeletal Development

Cited by 299 publications

References 46 publications

Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life

Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life

Mitogen-activated Protein Kinase p38 Mediates Regulation of Chondrocyte Differentiation by Parathyroid Hormone

Sox9 Family Members Negatively Regulate Maturation and Calcification of Chondrocytes through Up-Regulation of Parathyroid Hormone–related Protein

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