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The parathyroid hormone-related protein and Indian hedgehog feedback loop in the growth plate
1Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Insights
Indian hedgehog (IHH) and parathyroid hormone-related protein (PTHrP) regulate growth plate development. Disrupting their interaction leads to abnormal chondrocyte and osteoblast differentiation, highlighting IHH as a key regulator.
Area of Science:
- Skeletal Biology
- Developmental Biology
- Endocrinology
Background:
- Normal growth plate development depends on coordinated chondrocyte and osteoblast proliferation and differentiation.
- Indian hedgehog (IHH) and parathyroid hormone-related protein (PTHrP) form a negative feedback loop regulating chondrocyte differentiation pace.
- PTHrP maintains chondrocytes in a proliferative state, delaying IHH production.
Purpose of the Study:
- To investigate the roles of physiological levels of PTHrP and IHH in growth plate development.
- To elucidate the regulatory mechanisms of chondrocyte and osteoblast differentiation.
Main Methods:
- Generation of chimeric mice by injecting PTH/PTHrP receptor (-/-) embryonic stem (ES) cells into normal blastocysts.
- Analysis of growth plate structure and gene expression patterns in chimeric mice.
- Utilizing chimeras with combined PTH/PTHrP receptor (-/-) and IHH (-/-) ES cells.
Main Results:
- PTH/PTHrP receptor (-/-) cells differentiated prematurely within the growth plate.
- Wild-type cell columns and adjacent bone collars were elongated in chimeric mice.
- Altered IHH and PTHrP synthesis patterns were identified as the cause of these abnormalities.
Conclusions:
- Indian hedgehog (IHH) acts as a master regulator of both chondrocyte and osteoblast differentiation.
- The interplay between IHH and PTHrP is crucial for synchronizing and pacing chondrocyte differentiation.
- Disruption of this feedback loop leads to significant growth plate abnormalities.
Abstract:
Normal development of the growth plate requires coordinated proliferation and differentiation of chondrocytes and osteoblasts. In previous work, we have shown that Indian hedgehog (IHH), produced by prehypertrophic and hypertrophic chondrocytes, stimulates production of parathyroid hormone-related protein (PTHrP) by perichondrial and early chondrocytic cells. PTHrP then maintains chondrocytes in a proliferative, less differentiated state. Because this less differentiated state delays the production of IHH, IHH and PTHrP may participate in a negative feedback loop that synchronizes and determines the pace of differentiation of chondrocytes in the growth plate. To establish the roles of physiological levels of PTHrP and IHH, we have now injected PTH/PTHrP receptor (-/-) embryonic stem (ES) cells into normal blastocysts to generate mice with chimeric growth plates. The PTH/PTHrP receptor cells leave the proliferative cycle and differentiate prematurely in the middle of the normal proliferative columns. The columns of wild-type cells are longer than normal and the adjacent bone collar is also longer than normal. Patterns of gene expression and the use of chimeras using PTH/PTHrP receptor (-/-); IHH (-/-) ES cells suggest that modified patterns of IHH and PTHrP synthesis explain these abnormalities. Thus, IHH is a master regulator of both chondrocyte and osteoblast differentiation.