Aging is a main risk factor for osteoarthritis (OA) FoxO transcription factors protect against cellular and organismal aging, and FoxO expression in cartilage is reduced with aging and in OA To investigate the role of FoxO in cartilage, Col2Cre-FoxO1, 3, and 4 single knockout (KO) and triple KO mice (Col2Cre-TKO) were analyzed Articular cartilage in Col2Cre-TKO and Col2Cre-FoxO1 KO mice was thicker than in control mice at 1 or 2 months of age This was associated with increased proliferation of chondrocytes of Col2Cre-TKO mice in vivo and in vitro OA-like changes developed in cartilage, synovium, and subchondral bone between 4 and 6 months of age in Col2Cre-TKO and Col2Cre-FoxO1 KO mice Col2Cre-FoxO3 and FoxO4 KO mice showed no cartilage abnormalities until 18 months of age when Col2Cre-FoxO3 KO mice had more severe OA than control mice Autophagy and antioxidant defense genes were reduced in Col2Cre-TKO mice Deletion of FoxO1/3/4 in mature mice using Aggrecan(Acan)-CreERT2 (AcanCreERT-TKO) also led to spontaneous cartilage degradation and increased OA severity in a surgical model or treadmill running The superficial zone of knee articular cartilage of Col2Cre-TKO and AcanCreERT-TKO mice exhibited reduced cell density and markedly decreased Prg4 In vitro, ectopic FoxO1 expression increased Prg4 and synergized with transforming growth factor-β stimulation In OA chondrocytes, overexpression of FoxO1 reduced inflammatory mediators and cartilage-degrading enzymes, increased protective genes, and antagonized interleukin-1β effects Our observations suggest that FoxO play a key role in postnatal cartilage development, maturation, and homeostasis and protect against OA-associated cartilage damage

FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis

Osteoarthritis (OA) is an extremely prevalent age-related condition. The economic and societal burden due to the cost of symptomatic treatment, inability to work, joint replacement, and rehabilitation is huge and increasing. Currently, there are no effective medical therapies that delay or reverse the pathological manifestations of OA. Current treatment options are, without exception, focused on slowing down progression of the disease to postpone total joint replacement surgery for as long as possible and keeping the associated pain and joint immobility manageable. Alterations in the articular cartilage chondrocyte phenotype might be fundamental in the pathological mechanisms of OA development. In many ways, the changing chondrocyte phenotype in osteoarthritic cartilage resembles the process of endochondral ossification as seen, for instance, in developing growth plates. However, the relative contribution of endochondral ossification to the changing chondrocyte phenotype in the development and progression of OA remains poorly described. In this review, we will discuss the current knowledge regarding the cartilage endochondral phenotypic changes occurring during OA development and progression, as well as the molecular and environmental effectors driving these changes. Understanding how these molecular mechanisms determine the chondrocyte cell fate in OA will be essential in enabling cartilage regenerative approaches in future treatments of OA.

/pdf/recent-insights-into-the-contribution-of-the-changing-4o67rrqru5.pdf

Recent Insights into the Contribution of the Changing Hypertrophic Chondrocyte Phenotype in the Development and Progression of Osteoarthritis.

The objective of this study was to examine FoxO expression and FoxO function in meniscus. In menisci from human knee joints with osteoarthritis (OA), FoxO1 and 3 expression were significantly reduced compared with normal menisci from young and old normal donors. The expression of FoxO1 and 3 was also significantly reduced in mouse menisci during aging and OA induced by surgical meniscus destabilization or mechanical overuse. Deletion of FoxO1 and combined FoxO1, 3, and 4 deletions induced abnormal postnatal meniscus development in mice and these mutant mice spontaneously displayed meniscus pathology at 6 mo. Mice with Col2Cre-mediated deletion of FoxO3 or FoxO4 had normal meniscus development but had more severe aging-related damage. In mature AcanCreERT2 mice, the deletion of FoxO1, 3, and 4 aggravated meniscus lesions in all experimental OA models. FoxO deletion suppressed autophagy and antioxidant defense genes and altered several meniscus-specific genes. Expression of these genes was modulated by adenoviral FoxO1 in cultured human meniscus cells. These results suggest that FoxO1 plays a key role in meniscus development and maturation, and both FoxO1 and 3 support homeostasis and protect against meniscus damage in response to mechanical overuse and during aging and OA.

FOXO1 and FOXO3 transcription factors have unique functions in meniscus development and homeostasis during aging and osteoarthritis.

Our previous studies discovered that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR) and long-bone dysplasia in offspring rats, accompanied by maternal glucocorticoid over-exposure. This study is to explore whether intrauterine high glucocorticoid level can cause endochondral ossification retardation and clarify its molecular mechanism in PCE fetal rats. Pregnant Wistar rats were intragastrically administered 30 and 120 mg/kg day of caffeine during gestational days (GDs) 9–20, then collected fetal serum and femurs at GD20. In vitro, primary chondrocytes were treated with corticosterone (0–1250 nM), caffeine (0–100 μM), mitogen-inducible gene 6 (Mig-6) siRNA and epidermal growth factor receptor (EGFR) siRNA, respectively, or together. Results showed that the hypertrophic chondrocytes zone (HZ) of PCE fetal femur was widened. Meanwhile, the expression levels of chondrocytes terminal differentiation genes in the HZ were decreased, and the chondrocytes apoptosis rate in the HZ was decreased too. Furthermore, PCE upregulated Mig-6 and suppressed EGFR expression in the HZ. In vitro, a high-concentration corticosterone (1250 nM) upregulated Mig-6 expression, inhibit EGFR/c-Jun N-terminal kinase (JNK) signaling pathway and terminal differentiation genes expression in chondrocytes and reduced cell apoptosis, and these above alterations could be partly reversed step-by-step after Mig-6 and EGFR knockdown. However, caffeine concentration dependently increased chondrocyte apoptosis without significant changes in the expression of terminal differentiation genes. Collectively, PCE caused endochondral ossification retardation in the female fetal rats, and its main mechanism was associated with glucocorticoid (rather than caffeine)-mediated chondrocyte terminal differentiation suppression by the upregulation of Mig-6 and then inhibition of EGFR/JNK pathway-mediated chondrocyte apoptosis.

/pdf/glucocorticoid-mediates-prenatal-caffeine-exposure-induced-26tmmulh7s.pdf

Glucocorticoid mediates prenatal caffeine exposure-induced endochondral ossification retardation and its molecular mechanism in female fetal rats.

Ossification of the ligamentum flavum (OLF) is a common spinal disorder that causes myelopathy and radiculopathy. Non-coding RNAs (ncRNAs) are involved in numerous pathological processes; however, very few ncRNAs have been identified to be correlated with OLF. Here we compared the expression of lncRNA, mRNA, circRNA, and microRNA in OLF tissues from OLF patients and healthy volunteers through mRNA, lncRNA, and circRNA microarrays and microRNA sequencing. A total of 2,054 mRNAs, 2,567 lncRNAs, 627 circRNAs, and 28 microRNAs (miRNAs) were altered during the process of OLF. qPCR confirmed the differential expression of selected mRNAs and ncRNAs. An lncRNA-mRNA co-expression network, miRNA-mRNA target prediction network, and competing endogenous RNA (ceRNA) network of circRNA-miRNA-mRNA were constructed based on a correlation analysis of the differentially expressed RNA transcripts. Subsequently, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses for the differentially expressed mRNAs and the predicted miRNAs target genes were performed. In addition, a deregulated miRNA-19b-3p-based miRNA-circRNA-lncRNA-mRNA network was confirmed, by gain-of-function and loss-of-function experiments, to function in the process of ossification. Taken together, this study provides a systematic perspective on the potential function of ncRNAs in the pathogenesis of OLF.

A Transcriptome-Level Study Identifies Changing Expression Profiles for Ossification of the Ligamentum Flavum of the Spine

Osteoarthritis (OA) is the most common joint disease affecting close to 27 million Americans. The pathological change of OA joint is characterized by cartilage degradation and osteophyte formation that have been associated with OA initiation and progression respectively. Upon OA progression, articular chondrocytes undergo hypertrophic differentiation, a process usually occurs only in growth plate chondrocytes during endochondral ossification, suggesting a role of chondrocyte hypertrophy in OA pathogenesis. However, how altered chondrocyte hypertrophy, i.e. accelerated or delayed chondrocyte hypertrophy, influences OA development has not been fully elucidated. We have previously generated transgenic (TG) mice over-expressing Runx2, an essential transcription factor for chondrocyte hypertrophy, using hypertrophic chondrocyte-specific mouse type X collagen gene (Col10a1) control elements. These Col10a1-Runx2 TG mice show delayed chondrocyte hypertrophy and apoptosis in long bone sections of embryonic and new-born mice compared to their wild-type (WT) littermates. Here, we report further analysis of the skeletal phenotypes of these mice at postnatal stages. We have performed histological analysis of 1-month old TG and WT mice. Delayed chondrocyte hypertrophy was also observed in growth plate of TG mice. In addition, μCT analysis showed that the femur length was significantly shorter in TG mice (p = 0.033). Thinner cortical bone and markedly decreased BV/TV were also detected in TG mice compared to their WT littermates (p = 0.027), suggesting that delayed chondrocyte hypertrophy affects postnatal long bone development. Interestingly, histological analysis detected less articular cartilage absorption, while immunohistochemistry assay detected upregulated Sox9 expression in TG mouse joints compared to WT controls, implying that delayed chondrocyte hypertrophy may be OA protective. Indeed, we have performed Tgf-β1 injection and enforced uphill treadmill running (TTR model) to induce OA in TG and WT littermates. The results showed that WT littermates displayed characteristic pathology of fibrotic remodeling at the joint margins and focal cartilage erosion, while the joints in TG mice were essentially protected from remodeling responses, demonstrating that mice with delayed chondrocyte hypertrophy are not susceptible to developing OA. Further translational studies characterizing the role of chondrocyte hypertrophy during OA progression will facilitate identification of therapeutic targets to stop or slow down this degenerative and progressive human joint disease.

Col10a1-Runx2 transgenic mice with delayed chondrocyte maturation are less susceptible to developing osteoarthritis

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Col10a1-Runx2 transgenic mice with delayed chondrocyte maturation are less susceptible to developing osteoarthritis