PTHrP regulates growth plate chondrocyte differentiation and proliferation in a Gli3 dependent manner utilizing hedgehog ligand dependent and independent mechanisms

Mau, Elaine; Whetstone, Heather; Yu, Chunying; Hopyan, Sevan; Wunder, Jay S.; Alman, Benjamin A.

doi:10.1016/j.ydbio.2007.01.031

Cited by 53 publications

(55 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Examination of the growth plates of mice deficient in Gli2 and Gli3 treated with PTHrP and H89 suggests that PTHrP regulates chondrocyte proliferation through Gli3 in a ligand-independent, PKA-dependent manner 109 .…”

Section: Developmental Signaling Pathways In Post Natal Chondrocytesmentioning

confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

Self Cite

293

340

View full text Add to dashboard Cite

Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development. Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation; however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here I examined human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, I found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, Ishow in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runtrelated transcription factor-2 (Runx2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (Adamts5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.iii ACKNOWLEDGEMENTS

show abstract

Section: Developmental Signaling Pathways In Post Natal Chondrocytesmentioning

confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

Self Cite

293

340

View full text Add to dashboard Cite

show abstract

“…The effects of Pthlh on normal growth plate chondrocytes are mediated primarily by PKA (13,21,27). Treatment with the PKA inhibitor H-89 abolished the Pthlh effects on both wildtype and Col2a1-Cre;Sufu f/f explants (Fig.…”

Section: Methodsmentioning

confidence: 88%

“…Explant Cultures-Hind limb organ cultures from 16.5-day post-coitum embryos were established as described previously (3,4,13,16). Limbs were placed on a Nucleopore filter inside a well of a 24-well tissue culture plate, with the limb at the liquid/ air interface.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Suppressor of Fused (Sufu) Mediates the Effect of Parathyroid Hormone-like Hormone (Pthlh) on Chondrocyte Differentiation in the Growth Plate

Hsu¹,

Zhang²,

Cheng³

et al. 2012

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Hh and Pthlh signaling pathways play important roles in regulating growth plate chondrocyte differentiation. Results: Pthlh increases Sufu protein levels, and Sufu is required for the effect of Pthlh on chondrocyte differentiation. Conclusion: Pthlh regulates chondrocyte differentiation and Gli activity in a Sufu-dependent manner. Significance: The interaction between Pthlh, PKA, Sufu, and Gli transcriptional activities explains how Pthlh regulates chondrocyte differentiation.

show abstract

“…Ihh maintains the expression of parathyroid hormone-like peptide (Pthlh) (Mouse Genome Informatics) in the periarticular perichondrium (13), which then stimulates the proliferation and delays the hypertrophic differentiation of chondrocytes, in part through Gli3R (14,15). Ihh also promotes chondrocyte proliferation (13,16) and hypertrophic differentiation through Pthlh-independent mechanisms (17).…”

mentioning

confidence: 99%

Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

Cai

Liu

2016

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

View full text Add to dashboard Cite

Indian Hedgehog (Ihh) regulates chondrocyte and osteoblast differentiation through the Glioma-associated oncogene homolog (Gli) transcription factors. Previous in vitro studies suggested that Speckletype POZ protein (Spop), part of the Cullin-3 (Cul3) ubiquitin ligase complex, targets Gli2 and Gli3 for degradation and negatively regulates Hedgehog (Hh) signaling. In this study, we found defects in chondrocyte and osteoblast differentiation in Spop-null mutant mice. Strikingly, both the full-length and repressor forms of Gli3, but not Gli2, were up-regulated in Spop mutants, and Ihh target genes Patched 1 (Ptch1) and parathyroid hormone-like peptide (Pthlh) were down-regulated, indicating compromised Hh signaling. Consistent with this finding, reducing Gli3 dosage greatly rescued the Spop mutant skeletal defects. We further show that Spop directly targets the Gli3 repressor for ubiquitination and degradation. Finally, we demonstrate in a conditional mutant that loss of Spop results in brachydactyly and osteopenia, which can be rescued by reducing the dosage of Gli3. In summary, Spop is an important positive regulator of Ihh signaling and skeletal development.T he human skeleton provides essential mechanical support, mobility, and mineral storage critical for health (1). In development, most bones form through endochondral ossification in which chondrocytes in the growth plate proliferate, undergo hypertrophic differentiation, and secrete calcium-containing extracellular matrix (2). The osteoblasts in the perichondrium, a thin layer of tissue surrounding the cartilage, replace the dying chondrocytes and secrete more bone matrix. On the other hand, osteoclasts, derived from white blood cells, invade and digest bone matrix. The balance between the osteoblast and osteoclast activities allows calcium homeostatic control and bone health. In osteopenia and osteoporosis, conditions afflicting more than 10 million Americans, an abnormal decrease in osteoblast activity or increase in osteoclast activity results in the loss of bone mass (1, 3). Unfortunately, our understanding of these bone diseases has been hindered by incomplete knowledge in the molecular mechanisms underlying endochondral bone development and remodeling.Indian Hedgehog (Ihh), a member of the Hedgehog (Hh) family of signaling proteins, is essential for endochondral bone development (4). Ihh regulates gene expression through the Gli family of transcription factors, which act as both transcriptional activators and repressors (5). In the absence of Hh, efficient proteolytic processing turns Gli3 into a transcriptional repressor (Gli3R) whereas processing of Gli2 is rather inefficient (6-8). Hh inhibits Gli processing and converts the full-length Gli proteins into transcriptional activators. Both Gli2 and Gli3 play important roles in the regulation of bone formation downstream of Ihh (9-12).Ihh maintains the expression of parathyroid hormone-like peptide (Pthlh) (Mouse Genome Informatics) in the periarticular perichondrium (13), which then stimulates the prol...

show abstract

PTHrP regulates growth plate chondrocyte differentiation and proliferation in a Gli3 dependent manner utilizing hedgehog ligand dependent and independent mechanisms

Cited by 53 publications

References 47 publications

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Suppressor of Fused (Sufu) Mediates the Effect of Parathyroid Hormone-like Hormone (Pthlh) on Chondrocyte Differentiation in the Growth Plate

Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

Contact Info

Product

Resources

About