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Published on: February 24, 2017
Mitogen-activated protein kinase p38 mediates regulation of chondrocyte differentiation by parathyroid hormone
1Musculoskeletal Research Laboratory, Department of Orthopaedics and Rehabilitation, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Abstract:
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.
Insights
Parathyroid hormone (PTH) inhibits chondrocyte differentiation via p38 MAPK signaling. This pathway involves protein kinase C and regulates Bcl-2, preventing premature chondrocyte hypertrophy.
Area of Science:
- Endocrinology
- Cell Biology
- Skeletal Biology
Background:
- Parathyroid hormone (PTH) and its related peptide regulate endochondral ossification.
- The intracellular signaling pathway for PTH in chondrocytes is not fully understood.
Purpose of the Study:
- To elucidate the intracellular pathway mediating PTH/PTH-related peptide signals in chondrocytes.
- To identify the role of mitogen-activated protein kinase (MAPK) p38 in PTH signaling during chondrocyte differentiation.
Main Methods:
- Incubation of hypertrophic chondrocytes with PTH (1-34).
- Assessment of p38 kinase activity and its modulation by protein kinase C and A inhibitors.
- Analysis of Bcl-2 expression and collagen type X mRNA levels.
- Evaluation of cartilage matrix protein expression.
Main Results:
- PTH (1-34) inhibited p38 MAPK activity in a time- and dose-dependent manner.
- Protein kinase C, but not protein kinase A, was required for PTH-induced p38 MAPK inhibition.
- PTH and p38 MAPK inhibition up-regulated Bcl-2 expression.
- Inhibition of p38 MAPK decreased hypertrophic marker (collagen type X) and increased prehypertrophic marker (cartilage matrix protein) expression.
Conclusions:
- The p38 MAPK pathway is crucial for transducing PTH signals in chondrocytes.
- PTH signaling, mediated by p38 MAPK and involving protein kinase C, regulates chondrocyte differentiation.
- Inhibition of p38 MAPK by PTH prevents precocious chondrocyte hypertrophy by converting the hypertrophic phenotype to a prehypertrophic one.
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