Histone deacetylase 4 deletion results in abnormal chondrocyte hypertrophy and premature ossification from collagen type 2α1‑expressing cells

Abstract

Histone deacetylase 4 (Hdac4) plays a vital role in chondrocyte hypertrophy and bone formation. To investigate the function of Hdac4 in postnatal skeletal development, the present study developed lineage-specific HDAC4-knockout mice [collagen type 2α1 (col2α1)-cre, Hdac4 d/d mice] by crossing transgenic mice expressing Cre recombinase. Thus, a specific ablation of HDAC4 was performed in col2α1-expressing mice cells. The knee joints of Hdac4 fl/fl and col2α1-cre, Hdac4 d/d mice were analyzed at postnatal day (P)2-P21 using an in vivo bromodeoxyuridine (BrdU) assay, and Safranin O, Von Kossa and whole-body staining were used to evaluate the developmental growth plate, hypertrophic differentiation, mineralization and skeletal mineralization patterns. The trabecular bone was analyzed using microcomputed tomography. The expressions of Brdu, proliferating cell nuclear antigen (Pcna), matrix metalloproteinase (MMP)-13, runt-related transcription factor (runx)-2, osteoprotegerin (oPG), cd34, type X collagen (ColX), osteocalcin and Wnt5a were determined using immunohistochemistry, in situ hybridization (ISH) and reverse transcription-quantitative (rT-q)Pcr. The results demonstrated that Hdac4-null mice (Hdac4 d/d mice) were severely runted; these mice had a shortened hypertrophic zone (histopathological evaluation), accelerated vascular invasion and articular mineralization (Von Kossa staining), elevated expressions of MMP-13, runx2, oPG and cd34 (RT-qPCR and immunohistochemistry), downregulated expression of the proliferative marker Brdu and Pcna (immunohistochemistry), increased expression of colX and decreased expression of Wnt5a (iSH). in conclusion, chondrocyte-derived HDAC4 was responsible for regulating chondrocyte proliferation and differentiation as well as endochondral bone formation.

Regulation of FGF-2, FGF-18 and Transcription Factor Activity by Perlecan in the Maturational Development of Transitional Rudiment and Growth Plate Cartilages and in the Maintenance of Permanent Cartilage Homeostasis

“…HDAC4 promotes chromatin condensation, denying transcriptional factor access to DNA, repressively regulating chondrocyte maturation and the attainment of a pre-hypertrophic state. Deletion of HDAC4 results in premature calcification of cartilage [ 148 ]. This is supported by HDAC4 null mice which have severely runted frames, shortened growth plate hypertrophic zones, enhanced vascular invasion, and cartilage mineralization.…”

What Are the Potential Roles of Nuclear Perlecan and Other Heparan Sulphate Proteoglycans in the Normal and Malignant Phenotype

“…HDAC4 is the most extensively characterized member of the HDAC class IIa deacetylase enzyme family, which regulates signalling networks, affecting cartilage maturation. HDAC4 promotes chromatin condensation, reducing access of transcriptional factors to DNA and repressively regulating chondrocyte maturation and hypertrophy, and the deletion of HDAC4 results in premature calcification of cartilage [ 125 ]. HDAC4 null mice have squat runt-like frames—shortened growth plate hypertrophic zones, enhanced vascular invasion and cartilage mineralization.…”

Wnt3a knockdown promotes collagen type II expression in rat chondrocytes

“…Col2 forms the backbone for the construction of cartilage, which has structural and biochemical properties ( 16 , 17 ). A decrease in Col2 abundance may initiate and promote chondrocyte hypertrophy and OA progression ( 18 , 19 ). IL-1β can upregulate MMPs in the chondrocyte matrix, and MMPs can cause Col2 degradation ( 20 ).…”