Inflammatory bone loss associated with MFG‐E8 deficiency is rescued by teriparatide

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154457/1/fsb2fj201701238r-sup-0002.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154457/2/fsb2fj201701238r.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154457/3/fsb2fj201701238r-sup-0001.pd

Impact of proteoglycan‐4 and parathyroid hormone on articular cartilage

Proteoglycan‐4 ( Prg4 ) protects synovial joints from arthropathic changes by mechanisms that are incompletely understood. Parathyroid hormone (PTH), known for its anabolic actions in bone, increases Prg4 expression and has been reported to inhibit articular cartilage degeneration in arthropathic joints. To investigate the effect of Prg4 and PTH on articular cartilage, 16‐week‐old Prg4 mutant and wild‐type mice were treated with intermittent PTH (1–34) or vehicle control daily for six weeks. Analyses included histology of the knee joint, micro‐CT of the distal femur, and serum biochemical analysis of type II collagen fragments (CTX‐II). Compared to wild‐type littermates, Prg4 mutant mice had an acellular layer of material lining the surfaces of the articular cartilage and menisci, increased articular cartilage degradation, increased serum CTX‐II concentrations, decreased articular chondrocyte apoptosis, increased synovium SDF‐1 expression, and irregularly contoured subchondral bone. PTH‐treated Prg4 mutant mice developed a secondary deposit overlaying the acellular layer of material lining the joint surfaces, but PTH‐treatment did not alter signs of articular cartilage degeneration in Prg4 mutant mice. The increased joint SDF‐1 levels and irregular subchondral bone found in Prg4 mutant mice introduce novel candidate mechanisms by which Prg4 protects articular cartilage. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 183–190, 2013Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94686/1/22207_ftp.pd

Sclerostin Antibody as a Treatment for Osteogenesis Imperfecta.

Osteogenesis Imperfecta (OI) is a genetic collagen disorder characterized by increased fracture risk, and typically presents the strongest in children. Current efforts to reduce fracture rate in OI include treatment with anti-resorptive bisphosphonates. While bisphosphonate therapy has shown efficacy at increasing bone mass in the axial skeleton, there have not been consistent reductions in long bone fracture risk. New treatments which increase bone mass throughout the OI skeleton would be beneficial. Sclerostin antibody (Scl-Ab) is a potential candidate anabolic therapy for OI and functions by stimulating osteoblastic bone formation via the canonical wnt signaling pathway. We have characterized the use of Scl-Ab in a Brtl/+ mouse model of moderately severe Type IV OI. Treatment of rapidly growing, and adult, Brtl/+ mice demonstrate Scl-Ab stimulated bone formation, increased cortical and trabecular bone mass, and improved long bone strength. Using fluorescent guided analysis to control for tissue age, material composition (raman spectroscopy) and material property (nanoindentation) were also assessed. Scl-Ab did not effect the elastic modulus, did influence material composition, and differing patterns across tissue age were observed in rapidly growing vs adult animals. Collectively, these animal studies suggest that Scl-Ab may represent a new potential therapy for the treatment of OI.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/110366/1/bpsinder_1.pd

Macrophages: Their Emerging Roles in Bone

Macrophages are present in nearly all tissues and are critical for development, homeostasis, and regeneration. Resident tissue macrophages of bone, termed osteal macrophages, are recently classified myeloid cells that are distinct from osteoclasts. Osteal macrophages are located immediately adjacent to osteoblasts, regulate bone formation, and play diverse roles in skeletal homeostasis. Genetic or pharmacological modulation of macrophages in vivo results in significant bone phenotypes, and these phenotypes depend on which macrophage subsets are altered. Macrophages are also key mediators of osseous wound healing and fracture repair, with distinct roles at various stages of the repair process. A central function of macrophages is their phagocytic ability. Each day, billions of cells die in the body and efferocytosis (phagocytosis of apoptotic cells) is a critical process in both clearing dead cells and recruitment of replacement progenitor cells to maintain homeostasis. Recent data suggest a role for efferocytosis in bone biology and these new mechanisms are outlined. Finally, although macrophages have an established role in primary tumors, emerging evidence suggests that macrophages in bone support cancers which preferentially metastasize to the skeleton. Collectively, this developing area of osteoimmunology raises new questions and promises to provide novel insights into pathophysiologic conditions as well as therapeutic and regenerative approaches vital for skeletal health

Improved error resilience for volte and VoIP with 3GPP EVS channel aware coding

A highly error resilient mode of the newly standardized 3GPP EVS speech codec is described. Compared to the AMR-WB codec and other conversational codecs, the EVS channel aware mode offers significantly improved error resilience in voice communication over packet-switched networks such as Voiceover- IP (VoIP) and Voice-over-LTE (VoLTE). The error resilience is achieved using a form of in-band forward error correction. Source-controlled coding techniques are used to identify candidate speech frames for bitrate reduction, leaving spare bits for transmission of partial copies of prior frames such that a constant bit rate is maintained. The self-contained partial copies are used to improve the error robustness in case the original primary frame is lost or discarded due to late arrival. Subjective evaluation results from ITU-T P.800 Mean Opinion Score (MOS) tests are provided, showing improved quality under channel impairments as well as negligible impact to clean channel performance

Molecular diagnosis and novel genes and phenotypes in a pediatric thoracic insufficiency cohort

Abstract Thoracic insufficiency syndromes are a genetically and phenotypically heterogeneous group of disorders characterized by congenital abnormalities or progressive deformation of the chest wall and/or vertebrae that result in restrictive lung disease and compromised respiratory capacity. We performed whole exome sequencing on a cohort of 42 children with thoracic insufficiency to elucidate the underlying molecular etiologies of syndromic and non-syndromic thoracic insufficiency and predict extra-skeletal manifestations and disease progression. Molecular diagnosis was established in 24/42 probands (57%), with 18/24 (75%) probands having definitive diagnoses as defined by laboratory and clinical criteria and 6/24 (25%) probands having strong candidate genes. Gene identified in cohort patients most commonly encoded components of the primary cilium, connective tissue, and extracellular matrix. A novel association between KIF7 and USP9X variants and thoracic insufficiency was identified. We report and expand the genetic and phenotypic spectrum of a cohort of children with thoracic insufficiency, reinforce the prevalence of extra-skeletal manifestations in thoracic insufficiency syndromes, and expand the phenotype of KIF7 and USP9X-related disease to include thoracic insufficiency