Biology subjects

Ambrosio, F.

Publications and source records attributed to Ambrosio, F..

3 recordsLinked to original sources

bioRxiv2021

Meta-analysis and multi-omics to elucidate pathogenic mechanisms of age-related knee osteoarthritis

Increased mechanistic insight into the pathogenesis of knee osteoarthritis (KOA) is needed to develop efficacious disease-modifying treatments. Though age-related pathogenic mechanisms are most relevant to the great majority of KOA seen clinically, the bulk of our mechanistic understanding of KOA has been derived using surgically induced post-traumatic OA (PTOA) models. Here, we took an integrated approach of meta-analysis and multi-omics to elucidate pathogenic mechanisms of age-related KOA in murine model. Protein-level data together with transcriptomic profiling revealed inflammation, autophagy, and cellular senescence as primary hallmarks of age-related KOA. Importantly, the molecular profiles of aged cartilage were unique from those in PTOA, with only 1% overlap between the two. At the nexus of aging hallmarks, Advanced Glycation End-Product (AGE)/Receptor for AGE emerged as intrinsically linked to age-related KOA. This pathway was further validated by mass spectrometry. Collectively, these findings implicate dysregulation of AGE-RAGE signaling as a key driver of age-related KOA.

molecular biology↗

bioRxiv2021

Age-related increase in matrix stiffness downregulates α-Klotho in chondrocytes and induces cartilage degeneration

Enhanced mechanistic insight into age-related knee osteoarthritis (KOA) is an essential step to promote successful translation of animal research to bedside interventions. To this end, the goal of these studies was to interrogate molecular mechanisms driving age-related KOA in a mouse model and correspond findings to human knee cartilage. Unbiased mass spectrometry proteomics of cartilage tissue revealed PI3K/Akt signaling was the predominant pathway disrupted over time in male, but not female, mice. This finding was consistent with a significantly accelerated KOA progression in males when compared to female counterparts. In probing for upstream regulators of these age-dependent alterations, we found that -Klotho, a suppressor of PI3K/Akt signaling and potent longevity protein, significantly decreased with aging in both mouse and human knee cartilage. Upstream of these alterations, we found that age-related increases in matrix stiffness initiated a cascade of altered nuclear morphology and downregulated -Klotho expression, ultimately impairing chondrocyte health. Conversely, reducing matrix stiffness increased -Klotho expression in chondrocytes, thus enhancing their chondrogencity and cartilage integrity. Collectively, our findings establish a novel mechanistic link between age-related alterations in ECM biophysical properties and regulation of cartilage health by -Klotho.

molecular biology↗

bioRxiv2020

The biphasic and age-dependent impact of Klotho on hallmarks of aging and skeletal muscle function

Aging is accompanied by a disrupted information flow, which results from accumulation of molecular mistakes. These mistakes ultimately give rise to debilitating disorders such as skeletal muscle wasting, or sarcopenia. To estimate the growing "disorderliness" of the aging muscle system, we employed a statistical physics approach to estimate the state parameter, entropy, as a function of genes associated with hallmarks of aging. Although the most prominent structural and functional alterations were observed in the oldest old mice (27-29 months), we found that the escalating network entropy reached an inflection point at old age (22-24 months). To probe the potential for restoration of molecular "order" and reversal of the sarcopenic phenotype, we overexpressed the longevity protein, -Klotho. Klotho overexpression modulated genes representing all hallmarks of aging in both old and oldest-old mice. However, whereas Klotho improved strength in old mice, intervention failed to induce a benefit beyond the entropic tipping point.

physiology↗