Indian hedgehog: Its roles and regulation in endochondral bone development

Lai, Lo; Mitchell, Jane

doi:10.1002/jcb.20635

Cited by 94 publications

(63 citation statements)

References 49 publications

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“…The continued proliferation enables further synthesis of Ihh, thereby, creating a feedback loop that controls the pace of chondrocyte differentiation. This feedback loop has also been observed in the fetal mouse growth plate Lai and Mitchell, 2005;MacLean and Kronenberg, 2005). As the growth plate moves appositionally, the ability for PTH or PTHrP to diffuse to the prehypertrophic cells dwindles.…”

mentioning

confidence: 65%

PTH Stimulated Growth and Decreased Col‐X Deposition are Phosphotidylinositol‐3,4,5 Triphosphate Kinase and Mitogen Activating Protein Kinase Dependent in Avian Sterna

Harrington¹,

Coon²,

Kern³

et al. 2010

The Anatomical Record

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Type X collagen (Col-X) deposition is a marker of terminal differentiation during chondrogenesis, in addition to appositional growth and apoptosis. The parathyroid hormone/parathyroid hormone related peptide (PTH/PTHrP) receptor, or PPR, is a G-Protein coupled receptor (GPCR), which activates several downstream pathways, moderating chondrocyte differentiation, including suppression of Col-X deposition. An Avian sterna model was used to analyze the PPR GPCR downstream kinase role in growth rate and extracellular matrix (ECM) including Col-II, IX, and X. Phosphatidylinositol kinase (PI3K), mitogen activating protein kinase (MAPK) and protein kinase A (PKA) were inhibited with specific established inhibitors LY294002, PD98059, and H89, respectively to test the hypothesis that they could reverse/inhibit the PTH/PTHrP pathway. Excised E14 chick sterna were PTH treated with or without an inhibitor and compared to controls. Sternal length was measured every 24 hr. Cultured sterna were immuno-stained using specific antibodies for Col-II, IX, or X and examined via confocal microscopy. Increased growth in PTHtreated sterna was MAPK, PI3K, and PKA dose dependent, suggesting growth was regulated through multiple pathways. Col-X deposition was rescued in PTH-treated sterna in the presence of PI3K or MAPK inhibitors, but not with the PKA inhibitor. All three inhibitors moderately disrupted Col-II and Col-IX deposition. These results suggest that PTH can activate multiple pathways during chondrocyte differentiation. Anat Rec,

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mentioning

confidence: 65%

PTH Stimulated Growth and Decreased Col‐X Deposition are Phosphotidylinositol‐3,4,5 Triphosphate Kinase and Mitogen Activating Protein Kinase Dependent in Avian Sterna

Harrington¹,

Coon²,

Kern³

et al. 2010

The Anatomical Record

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“…The abnormalities of the Pkdcc Ϫ/Ϫ mice are different from those seen in mouse mutants of genes essential for bone differentiation, such as Sox9 (Bi et al, 1999), Bmp5 (Kingsley et al, 1992), Pthrp (Lai and Mitchell, 2005), and Cbfa1 (Takeda et al, 2001). These mutants fail to undergo mesenchymal condensation, hypertrophy, or osteogenesis.…”

Section: Comparison With Other Mutant Micementioning

confidence: 91%

“…HCs synthesize type X collagen, undergo mineralization, and attract blood vessels and osteoclasts. HC development is regulated by the transcription factor Cbfa1/Runx2 (Inada et al, 1999;Takeda et al, 2001), and by the interaction of two signaling molecules, Ihh and PTHrP (Lai and Mitchell, 2005). Perichondrial cells, which are adjacent to the HCs, become osteoblasts and form the bone collar.…”

Section: Introductionmentioning

confidence: 99%

Short limbs, cleft palate, and delayed formation of flat proliferative chondrocytes in mice with targeted disruption of a putative protein kinase gene, Pkdcc (AW548124)

Imuta

Nishioka²,

Kanazawa

et al. 2008

Developmental Dynamics

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During long bone development, round proliferative chondrocytes (RPCs) differentiate into flat proliferative chondrocytes (FPCs), and then into hypertrophic chondrocytes (HCs). FPCs and HCs support longitudinal bone growth. Here we show that a putative protein kinase gene, Pkdcc (AW548124), is required for longitudinal bone growth. We originally found Pkdcc expressed in the head organizer, but it is also expressed throughout embryogenesis and in various adult tissues. Pkdcc ؊/؊ embryos had no head organizer-related defects, but showed various morphological abnormalities at birth, including short limbs, cleft palate, sternal dysraphia, and shortened intestine. In the long bones of the limbs, only the mineralized regions were shortened, and the cartilage length was normal. In the humerus, Pkdcc was strongly expressed in the early FPCs, and FPC and HC formation was delayed in Pkdcc ؊/؊ mutants. Together, these data indicate that Pkdcc encodes a protein kinase that is required for the appropriate timing of FPC differentiation. Developmental Dynamics 238:210 -222, 2009.

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“…After 3 days, at day 7 of culture, for investigating the expression of collagen type II and aggrecan, as markers for early differentiation (Sive et al 2002), and at day 14, for investigating the expression of collagen type X, Ihh, and ALP, as markers for terminal differentiation (Lai & Mitchell 2005), cells were serumstarved for 12 h and stimulated with 100 ng/ml IGF-I for 12 additional hours, in the presence or absence of the indicated inhibitors, and then harvested. RNA was isolated by using the RNeasy mini columns (Qiagen) and reverse transcribed by using Moloney Murine Leukemia Virus reverse transcriptase and oligo(dt)/ random hexamer primers (10:1) from Applied Biosystems (Darmstadt, Germany).…”

Section: Quantitative Rt-pcrmentioning

confidence: 99%

Signaling mechanisms leading to regulation of proliferation and differentiation of the mesenchymal chondrogenic cell line RCJ3.1C5.18 in response to IGF-I

Ciarmatori¹,

Kiepe²,

Haarmann³

et al. 2007

Journal of Molecular Endocrinology

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Since IGF-I is an important chondrocyte growth factor, we sought to examine the intracellular mechanisms by which it exerts two of its pivotal effects, stimulation of proliferation and differentiation. We used the mesenchymal chondrogenic cell line RCJ3.1C5.18, which progresses spontaneously to differentiated growth plate chondrocytes. This differentiation process could be enhanced by exogenous IGF-I. Pharmacological inhibition of the phosphatidylinositol-3 (PI-3) kinase by LY294002, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)1/2 by U0126, the protein kinase (PK) A pathway by H-89 or KT5720, and the PKC pathway by bisindolylmaleimide suppressed IGF-I-stimulated cell proliferation. In contrast, IGF-I-enhanced early cell differentiation, as assessed by collagen type II and aggrecan gene expression, was not affected by MAPK/ERK1/2 pathway inhibition, but significantly diminished by inhibition of the PI-3 kinase, the PKC and the PKA pathway. Moreover, terminal differentiation of chondrocytes in response to IGF-I, as assessed by gene expression of alkaline phosphatase, Indian hedgehog, and collagen type X, were only interrupted by PI-3 kinase pathway inhibition. In conclusion, IGF-I exerts its differential effect on chondrocyte proliferation vs differentiation through the use of at least four partially interacting intracellular signaling pathways, whose activity is temporarily regulated. When chondrocytes progress from proliferating cells to early and terminal differentiating cells, they progressively inactivate IGF-I-related intracellular signaling pathways. This mechanism might be essential for the complex and cell stage-specific anabolic action of IGF-I in the growth plate.

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Indian hedgehog: Its roles and regulation in endochondral bone development

Cited by 94 publications

References 49 publications

PTH Stimulated Growth and Decreased Col‐X Deposition are Phosphotidylinositol‐3,4,5 Triphosphate Kinase and Mitogen Activating Protein Kinase Dependent in Avian Sterna

PTH Stimulated Growth and Decreased Col‐X Deposition are Phosphotidylinositol‐3,4,5 Triphosphate Kinase and Mitogen Activating Protein Kinase Dependent in Avian Sterna

Short limbs, cleft palate, and delayed formation of flat proliferative chondrocytes in mice with targeted disruption of a putative protein kinase gene, Pkdcc (AW548124)

Signaling mechanisms leading to regulation of proliferation and differentiation of the mesenchymal chondrogenic cell line RCJ3.1C5.18 in response to IGF-I

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