Chondrocyte hypertrophy represents a crucial turning point during endochondral bone development. This process is tightly regulated by various factors, constituting a regulatory network that maintains normal bone development. Histone deacetylase 4 (HDAC4) is the most well-characterized member of the HDAC class IIa family and participates in different signalling networks during development in various tissues by promoting chromatin condensation and transcriptional repression. Studies have reported that HDAC4-null mice display premature ossification of developing bones due to ectopic and early-onset chondrocyte hypertrophy. Overexpression of HDAC4 in proliferating chondrocytes inhibits hypertrophy and ossification of developing bones, which suggests that HDAC4, as a negative regulator, is involved in the network regulating chondrocyte hypertrophy. Overall, HDAC4 plays a key role during bone development and disease. Thus, understanding the role of HDAC4 during chondrocyte hypertrophy and endochondral bone formation and its features regarding the structure, function, and regulation of this process will not only provide new insight into the mechanisms by which HDAC4 is involved in chondrocyte hypertrophy and endochondral bone development, but will also create a platform for developing a therapeutic strategy for related diseases. Cite this article:Bone Joint Res. 2020;9(2):82–89

Aims. To explore the novel molecular mechanisms of histone deacetylase 4 (HDAC4) in chondrocytes via RNA sequencing (RNA-seq) analysis. Methods. Empty adenovirus (EP) and a HDAC4 overexpression adenovirus were transfected into cultured human chondrocytes. The cell survival rate was examined by real-time cell analysis (RTCA) and EdU and flow cytometry assays. Cell biofunction was detected by Western blotting. The expression profiles of messenger RNAs (mRNAs) in the EP and HDAC4 transfection groups were assessed using whole-transcriptome sequencing (RNA-seq). Volcano plot, Gene Ontology, and pathway analyses were performed to identify differentially expressed genes (DEGs). For verification of the results, the A289E/S246/467/632 A sites of HDAC4 were mutated to enhance the function of HDAC4 by increasing HDAC4 expression in the nucleus. RNA-seq was performed to identify the molecular mechanism of HDAC4 in chondrocytes. Finally, the top ten DEGs associated with ribosomes were verified by quantitative polymerase chain reaction (QPCR) in chondrocytes, and the top gene was verified both in vitro and in vivo. Results. HDAC4 markedly improved the survival rate and biofunction of chondrocytes. RNA-seq analysis of the EP and HDAC4 groups showed that HDAC4 induced 2,668 significant gene expression changes in chondrocytes (1,483 genes upregulated and 1,185 genes downregulated, p < 0.05), and ribosomes exhibited especially large increases. The results were confirmed by RNA-seq of the EP versus mutated HDAC4 groups and the validations in vitro and in vivo. Conclusion. The enhanced ribosome pathway plays a key role in the mechanism by which HDAC4 improves the survival rate and biofunction of chondrocytes. Cite this article: Bone Joint Res 2023;12(7):433–446

Background. Long-term glucocorticoid treatment increases incidence of osteoporotic or osteonecrotic disorders. Excessive bone loss and marrow fat accumulation are prominent features of glucocorticoid-induced osteoporosis. MicroRNA-29 (miR-29) family members reportedly modulate lineage commitment of stem cells. This study was undertaken to define the biological roles of miR-29a in skeletal and fat metabolism in the pathogenesis of glucocorticoid-induced osteoporosis. Methods. Osteoblast-specific miR-29a transgenic mice (Tg) driven by osteocalcin promoter (C57BL/6JNarl-TgOCN-mir29a) or wild-type (WT) mice were given methylprednisolone. Bone mass, trabecular and cortical bone microarchitecture were assessed by μCT. Comparative mRNA and protein expression was quantified by RT-PCR and immunoblotting. Primary bone-marrow mesenchymal cells were isolated for elucidating ex vivo osteogenic and adipogenic differentiation capacity. Results. Decremented miR-29a expression was associated with severe skeletal deterioration and excessive marrow adipogenesis in glucocorticoid-induced osteoporosis bone tissue. Tg mice had high bone mass, spacious trabecular bone and thick cortical bone microstructure. Tg mice also had modest responses to the deleterious actions of glucocorticoid on trabecular microstructure and histomorphological characteristics, mineral acquisition and attenuated marrow fat deposition and osteoclast resorption. Ex vivo, miR-29a overexpression promoted bone-marrow mesenchymal progenitor cells differentiation towards osteogenic cells and away from adipogenic lineage cells. Mechanistically, miR-29a via inhibiting histone deacetylase 4 (HDAC4) actions restored acetylation states of osteogenic regulators Runx2 and β-catenin and decreased osteoclastogenic factor RANKL and adipokine leptin expression in bone microenvironments. Conclusions. Glucocorticoid suppression of miR-29a disintegrates the homeostasis between osteogenic and adipogenic activities, thereby impairs bone formation and skeletal integrity. By suppressing HDAC4, miR-29a stabilizes Runx2 and β-catenin signalling that counteracts the adverse effects of glucocorticoid on bone mass and marrow adiposity. This study unveils the anabolic roles of miR-29a in the progression of glucocorticoid-induced bone loss. Sustained miR-29a action is beneficial for protecting against osteoporosis and excessive marrow adipogenesis. Level of evidence. I

Aims

Long non-coding RNAs (lncRNAs) act as crucial regulators in osteoporosis (OP). Nonetheless, the effects and potential molecular mechanism of lncRNA PCBP1 Antisense RNA 1 (PCBP1-AS1) on OP remain largely unclear. The aim of this study was to explore the role of lncRNA PCBP1-AS1 in the pathogenesis of OP.

MicroRNAs (miRNAs) are a class of small non-coding RNAs that have emerged as potential predictive, prognostic, and therapeutic biomarkers, relevant to many pathophysiological conditions including limb immobilization, osteoarthritis, sarcopenia, and cachexia. Impaired musculoskeletal homeostasis leads to distinct muscle atrophies. Understanding miRNA involvement in the molecular mechanisms underpinning conditions such as muscle wasting may be critical to developing new strategies to improve patient management. MicroRNAs are powerful post-transcriptional regulators of gene expression in muscle and, importantly, are also detectable in the circulation. MicroRNAs are established modulators of muscle satellite stem cell activation, proliferation, and differentiation, however, there have been limited human studies that investigate miRNAs in muscle wasting. This narrative review summarizes the current knowledge as to the role of miRNAs in the skeletal muscle differentiation and atrophy, synthesizing the findings of published data.

Cite this article: Bone Joint Res 2020;9(11):798–807.

Objectives

This study looked to analyse the expression levels of microRNA-140-3p and microRNA-140-5p in synovial fluid, and their correlations to the severity of disease regarding knee osteoarthritis (OA).