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Mitogen-activated protein kinase p38 induces HDAC4 degradation in hypertrophic chondrocytes
Jingming Zhou1, Pengcui Li1,2, Qian Chen1
1Department of Orthopaedics, Warren Alpert Medical School of Brown University/Rhode Island Hosptal, Coro West, Suite 402H, 1 Hoppin Street, Providence RI 02903.
Insights
Mitogen-activated protein kinase p38 (MAPK p38) promotes histone deacetylase 4 (HDAC4) degradation via caspase activation. This process releases Runx2, promoting chondrocyte hypertrophy and bone formation.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Histone deacetylase 4 (HDAC4) inhibits chondrocyte hypertrophy by binding to Runx2.
- Regulation of HDAC4 stability during growth plate development is not well understood.
Purpose of the Study:
- To investigate the regulation of HDAC4 expression and stability during chondrocyte hypertrophy.
- To elucidate the role of MAPK p38 and caspases in HDAC4 degradation.
Main Methods:
- Inhibition of MAPK p38 using dominant-negative p38 or p38 inhibitors.
- Mutation of a potential caspase cleavage site (Asp289) in HDAC4.
- Utilizing constitutively active MAPK kinase 6 transgenic mice.
- Assessing caspase-3 activity and HDAC4 degradation in chondrocytes.
- Analyzing Runx2 promoter activity.
Main Results:
- MAPK p38 inhibition prevented HDAC4 degradation.
- Mutating the Asp289 cleavage site stabilized HDAC4.
- Constitutively active p38 transgenic mice showed decreased HDAC4 levels.
- p38 activation stimulated caspase-3 activity, leading to HDAC4 degradation.
- Inhibition of p38 or caspases reduced HDAC4 degradation.
- HDAC4 dose-dependently inhibited Runx2 activity; caspase inhibitors enhanced this inhibition.
Conclusions:
- MAPK p38 signaling promotes HDAC4 degradation through caspase-mediated cleavage.
- HDAC4 degradation by p38-activated caspases releases Runx2.
- This pathway is crucial for promoting chondrocyte hypertrophy and bone formation.
Abstract:
Histone deacetylase 4 (HDAC4) is a critical negative regulator for chondrocyte hypertrophy by binding to and inhibiting Runx2, a critical transcription factor for chondrocyte hypertrophy. It is unclear how HDAC4 expression and stability are regulated during growth plate development. We report here that inhibition of mitogen-activated protein kinase (MAPK) p38 by dominant negative p38 or p38 inhibitor prevents HDAC4 degradation. Mutation of a potential caspase-2 and 3 cleavage site Asp289 stabilizes HDAC4 in chondrocytes. In contrast, constitutively active MAPK kinase 6 (constitutive activator of p38) transgenic mice exhibit decreased HDAC4 content in vivo. We also observed that p38 stimulates caspase-3 activity in chondrocytes. Inhibition of p38 or caspases reduced HDAC4 degradation. HDAC4 inhibited Runx2 promoter activity in a dose-dependent manner and caspase inhibitors further enhanced this inhibition by preventing HDAC4 degradation. Overall, these results demonstrate that p38 promotes HDAC4 degradation by increasing caspase-mediated cleavage, which releases Runx2 from a repressive influence of HDAC4 and promotes the chondrocyte hypertrophy and bone formation.
