YAP/TAZ in Bone and Cartilage Biology

YAP and TAZ were initially described as the main regulators of organ growth during development and more recently implicated in bone biology. YAP and TAZ are regulated by mechanical and cytoskeletal cues that lead to the control of cell fate in response to the cellular microenvironment. The mechanical component represents a major signal for bone tissue adaptation and remodelling, so YAP/TAZ contributes significantly in bone and cartilage homeostasis. Recently, mice and cellular models have been developed to investigate the precise roles of YAP/TAZ in bone and cartilage cells, and which appear to be crucial. This review provides an overview of YAP/TAZ regulation and function, notably providing new insights into the role of YAP/TAZ in bone biology.

AMPK Signaling in Energy Control, Cartilage Biology, and Osteoarthritis

The adenosine monophosphate (AMP)–activated protein kinase (AMPK) was initially identified as an enzyme acting as an “energy sensor” in maintaining energy homeostasis via serine/threonine phosphorylation when low cellular adenosine triphosphate (ATP) level was sensed. AMPK participates in catabolic and anabolic processes at the molecular and cellular levels and is involved in appetite-regulating circuit in the hypothalamus. AMPK signaling also modulates energy metabolism in organs such as adipose tissue, brain, muscle, and heart, which are highly dependent on energy consumption via adjusting the AMP/ADP:ATP ratio. In clinics, biguanides and thiazolidinediones are prescribed to patients with metabolic disorders through activating AMPK signaling and inhibiting complex I in the mitochondria, leading to a reduction in mitochondrial respiration and elevated ATP production. The role of AMPK in mediating skeletal development and related diseases remains obscure. In this review, in addition to discuss the emerging advances of AMPK studies in energy control, we will also illustrate current discoveries of AMPK in chondrocyte homeostasis, osteoarthritis (OA) development, and the signaling interaction of AMPK with other pathways, such as mTOR (mechanistic target of rapamycin), Wnt, and NF-κB (nuclear factor κB) under OA condition.

Nanoliposomes from Agro-Resources as Promising Delivery Systems for Chondrocytes

Investigations in cartilage biology have been hampered by the limited capacity of chondrocytes, especially in rats and humans, to be efficiently transfected. Liposomes are a promising delivery system due to their lipid bilayer structure similar to a biological membrane. Here we used natural rapeseed lecithin, which contains a high level of mono- and poly-unsaturated fatty acids, to evaluate the cytocompatibility of these phospholipids as future potential carriers of biomolecules in joint regenerative medicine. Results show that appropriate concentrations of nanoliposome rapeseed lecithin under 500 µg/mL were safe for chondrocytes and did not induce any alterations of their phenotype. Altogether, these results sustain that they could represent a novel natural carrier to deliver active substances into cartilage cells.

The scinderin gene (SCIN) is the direct target of miR3085-3p in chondrocytes

MiR-3085-3p was shown to play a crucial role in cartilage biology, with potential impacts in osteoarthritis (OA). Insight into this miRNA function could be of practical importance for future miRNA-based therapy, however, little is known regarding the biological roles of this miRNA. The physiologic function of an individual miRNA is dictated through its mRNA targets, and as SCIN (scinderin, also known as adseverin) was reported to be involved in chondrocyte differentiation, maturation, and phenotype maintenance, this study aimed to prove SCIN is a direct target of miRNA-3085-3p. Bioinformatics algorithms were utilized for predicting their interacting sites. Gain- and loss-of-function experiments with miRNA-3085-3p were performed and SCIN expression was measured by real-time RT-PCR. SCIN 3?UTR regions harboring either the miR-3085-3p seed site or its mutant version were cloned into pmirGLO downstream of a reporter firefly luciferase encoding gene. The effect of miR-3085-3p on this region was determined by the luciferase assay. Four binding sites of miR-3085-3p in SCIN 3?UTR were identified. SCIN expression level was found to be inversely correlated with the level of miRNA-3085-3p. MiR3085-3p directly binds to its binding sites in SCIN 3? UTR. These data suggest that SCIN is the direct target of miR-3085-3p in chondrocyte cells.

TGFβ/BMP Signaling Pathway in Cartilage Homeostasis

Cartilage homeostasis is governed by articular chondrocytes via their ability to modulate extracellular matrix production and degradation. In turn, chondrocyte activity is regulated by growth factors such as those of the transforming growth factor β (TGFβ) family. Members of this family include the TGFβs, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs). Signaling by this protein family uniquely activates SMAD-dependent signaling and transcription but also activates SMAD-independent signaling via MAPKs such as ERK and TAK1. This review will address the pivotal role of the TGFβ family in cartilage biology by listing several TGFβ family members and describing their signaling and importance for cartilage maintenance. In addition, it is discussed how (pathological) processes such as aging, mechanical stress, and inflammation contribute to altered TGFβ family signaling, leading to disturbed cartilage metabolism and disease.

Circadian time series proteomics reveals daily dynamics in cartilage physiology

ObjectivesArticular cartilage undergoes cyclical heavy loading and low load recovery during the 24-hour day/night cycle. We investigated the daily changes of protein abundance in mouse femoral head articular cartilage by performing 24-hour time-series proteomics study.MethodsTandem mass spectrometry analysis was used to quantify proteins extracted from mouse cartilage. Bioinformatics analysis was performed to quantify rhythmic changes in protein abundance. Primary chondrocytes were isolated and cultured for independent validation of selected rhythmic proteins.Results145 rhythmic proteins were detected. Among these were key cartilage molecules including CCN2, MATN1, PAI-1 and PLOD1 & 2. Pathway analysis revealed that proteins related to protein synthesis, cytoskeleton and glucose metabolism exhibited time-of-day dependent peaks in their abundance. Meta-analysis of published proteomics datasets from articular cartilage revealed that numerous rhythmic proteins were dysregulated in osteoarthritis and/or ageing.ConclusionsOur circadian proteomics study revealed that articular cartilage is a much more dynamic tissue than previously thought. Chondrocytes exhibit circadian rhythms not only in gene expression but also in protein abundance. Our results clearly call for the consideration of circadian timing in understanding cartilage biology, osteoarthritis pathogenesis, treatment strategies and biomarker detection.