A Na\u3csup\u3e+\u3c/sup\u3e/K\u3csup\u3e+\u3c/sup\u3e ATPase Pump Regulates Chondrocyte Differentiation and Bone Length Variation in Mice

The genetic and developmental mechanisms involved in limb formation are relatively well documented, but how these mechanisms are modulated by changes in chondrocyte physiology to produce differences in limb bone length remains unclear. Here, we used high throughput RNA sequencing (RNAseq) to probe the developmental genetic basis of variation in limb bone length in Longshanks, a mouse model of experimental evolution. We find that increased tibia length in Longshanks is associated with altered expression of a few key endochondral ossification genes such as Npr3, Dlk1, Sox9, and Sfrp1, as well reduced expression of Fxyd2, a facultative subunit of the cell membrane-bound Na+/K+ ATPase pump (NKA). Next, using murine tibia and cell cultures, we show a dynamic role for NKA in chondrocyte differentiation and in bone length regulation. Specifically, we show that pharmacological inhibition of NKA disrupts chondrocyte differentiation, by upregulating expression of mesenchymal stem cell markers (Prrx1, Serpina3n), downregulation of chondrogenesis marker Sox9, and altered expression of extracellular matrix genes (e.g., collagens) associated with proliferative and hypertrophic chondrocytes. Together, Longshanks and in vitro data suggest a broader developmental and evolutionary role of NKA in regulating limb length diversity

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Chondrocyte hypertrophy in skeletal development, growth, and disease

Most of our bones form through the process of endochondral ossification, which is tightly regulated by the activity of the cartilage growth plate. Chondrocyte maturation through the various stages of growth plate physiology ultimately results in hypertrophy. Chondrocyte hypertrophy is an essential contributor to longitudinal bone growth, but recent data suggest that these cells also play fundamental roles in signaling to other skeletal cells, thus coordinating endochondral ossification. On the other hand, ectopic hypertrophy of articular chondrocytes has been implicated in the pathogenesis of osteoarthritis. Thus, a better understanding of the processes that control chondrocyte hypertrophy in the growth plate as well as in articular cartilage is required for improved management of both skeletal growth disorders and osteoarthritis. This review summarizes recent findings on the regulation of hypertrophic chondrocyte differentiation, the cellular mechanisms involved in hypertrophy, and the role of chondrocyte hypertrophy in skeletal physiology and pathophysiology. © 2014 Wiley Periodicals, Inc

Nuclear receptors as potential drug targets in osteoarthritis

Osteoarthritis is amongst the major causes of disability worldwide, but no medications that can slow or stop progression of this disorder have been identified. Recent evidence suggests roles for a variety of members of the nuclear receptor family of ligand-activated transcription factors in various forms of osteoarthritis. Since nuclear receptors are amongst the major classes of drug targets, these studies suggest that modulators of nuclear receptor activity might provide novel strategies to treat osteoarthritis. This review focuses on recent advances in our understanding of the role of nuclear receptors in osteoarthritis onset and progression, as well as their therapeutic implications. Future studies should continue to examine the possible roles of additional nuclear receptors in the pathophysiology of different types of osteoarthritis

Scientific Overview on CSCI-CITAC Annual General Meeting and 2018 Young Investigators’ Forum

The 2018 Annual General Meeting (AGM) and Young Investigators’ Forum (YIF) of the Canadian Society of Clinician Investigators (CSCI) and Clinician Investigator Trainee Association of Canada/Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was held in Toronto, Ontario on November 19–20, 2018, in conjunction with the University of Toronto Clinician Investigator Program Research Day. The theme for the meeting was “Prepare for Success—Things to Master Now for Clinician Scientists in Training”; with lectures and workshops that were designed to provide knowledge and hands-on skills to navigate life as a clinician investigator. The opening remarks were by Jason Berman (President of CSCI), Josh Abraham (President of CITAC/ACCFC) and Nicola Jones (University of Toronto Clinician Investigator Symposium Chair). The keynote speakers were Dr. Ruth Ann Marrie (University of Manitoba), who received the Distinguished Scientist Award, Dr. Davinder Jassal (University of Manitoba), who received the CSCI-RCPSC Henry Friesen Award, and Dr. Aleixo Muise (University of Toronto), who received the Joe Doupe Young Investigator Award. Dr. Minna Woo (University of Toronto), Canada Research Chair in Diabetes Signal Transduction, delivered the keynote lecture “From Onion Cells to Single Cell Seq—A Constant Change in Lenses: A perspective of an evolving clinician scientist”. The workshops, focusing on career development for clinician-scientists, were hosted by Drs. Robert Chen, Stephen Juvet, Lorraine Kalia, Phyllis Billia, Neil Goldenberg, Nicola Jones, Srdjanaa Filipovic, Jason Berman, Josh Abraham, Melanie Szweras, Joseph Ferenbok and Uri Tabori. The AGM also included presentations from clinician investigator trainees from across the country, and these abstracts are summarized in this review. Over 80 abstracts were showcased at this year’s meeting during the poster session, with six outstanding abstracts selected for oral presentations during the President’s Forum