BoneKEy osteovision最新文献

Bone responds to supraphysiological mechanical loads by increasing bone formation. Depending on the applied strain magnitude (and other loading parameters) the response can be either adaptive (mostly lamellar bone) or injury (mostly woven bone). Seminal studies of Hert, Lanyon, and Rubin originally established the basic "rules" of bone mechanosensitivity. These were reinforced by subsequent studies using non-invasive rodent loading models, most notably by Turner et al. More recent work with these models have been able to explore the structural, transcriptional, and molecular mechanisms which distinguish the two responses (lamellar vs. woven). Wnt/Lrp signaling has emerged as a key mechanoresponsive pathway for lamellar bone. However, there is still much to study with regard to effects of ageing, osteocytes, other signaling pathways, and the molecular regulation that modulates lamellar vs. woven bone formation. This review summarizes not only the historical findings but also the current data for these topics.

Recently, methicillin-resistant Staphylococcus aureus (MRSA) has surpassed HIV as the most deadly pathogen in the United States, accounting for over 100,000 deaths per year. In orthopedics, MRSA osteomyelitis has become the greatest concern in patient care, despite the fact that improvements in surgical technique and aggressive antibiotic prophylaxis have decreased the infection rate for most procedures to less than 5%. This great concern is largely due to the very poor outcomes associated with MRSA osteomyelitis, which includes 30-50% failure rates for revision surgery. Thus, there is a need to develop additional therapeutic interventions such as passive immunization, particularly for immunocompromised patients and the elderly who are typically poor responders to active vaccines. Using a novel murine model of implant-associated osteomyelitis in which a stainless steel pin is coated with bioluminescent S. aureus and implanted transcortically through the tibial metaphysis, we discovered that mice protect themselves from this infection by mounting a specific IgG2b response against the peptidoglycan hydrolase, glucosaminidase (Gmd), an enzyme involved in cell wall digestion during binary fission. Since this subunit of S. aureus autolysin is essential for bacterial growth, and no genetic variation has been identified among clinical strains, we propose that monoclonal antibodies against this enzyme would have multiple mechanisms of action, including promotion of opsonophagocytosis and direct inhibition of enzyme function. Here we review the field of MRSA osteomyelitis and our research to date on the development of an anti-Gmd passive immunotherapy.

Pluripotent mesenchymal stem cells (MSCs) are considered ideal therapeutic targets in regenerative medicine, as they hold the capacity to differentiate into higher order connective tissues. The potential to harness MSCs for disease treatment and acceleration of repair will ultimately depend on an improved understanding of how physical and/or chemical signals regulate their activity, and the ability of exogenous stimuli to enhance MSC proliferation and define MSC fate. Recent appreciation that bone marrow osteoprogenitors are inversely proportional to adipocyte precursors suggests that their shared progenitor, the MSC, will commit to one lineage at the cost of the other. This interrelationship may contribute to the phenotype of sedentary subjects who have more fat and less bone, while conversely, to the outcome of exercise being less fat and more bone. Mechanical biasing of MSC lineage selection suggests that physical signals may influence the quantity of both fat and bone through developmental, as well as metabolic or adaptive pathways. Considered with the recent finding that low magnitude mechanical signals (LMMS) suppress the development of subcutaneous and visceral fat without elevating energy expenditure, this indicates that MSCs are ideally positioned as mechanosensitive elements central to musculoskeletal adaptation, but that the signals needn't be large to be influential. The biasing of MSC differentiation by mechanical signals represents a unique means by which adiposity can be inhibited while simultaneously promoting a better skeleton, and may provide the basis for a safe, non-invasive, non-pharmacologic strategy to prevent both obesity and osteoporosis, yet uniquely - without targeting the resident fat or bone cell.

There may be no single mechanoreceptor in osteocytes, but instead a combination of events that has to be triggered for mechanosensation and transduction of signal to occur. Possibilities include shear stress along dendritic processes and/or the cell body, cell deformation in response to strain, and primary cilia. These events could occur independently or simultaneously to activate mechanotransduction. Signal initiators include calcium channel activation and ATP, nitric oxide, and prostaglandin release. Means of signal transfer include gap junctions and hemichannels, and the release of signaling molecules into the bone fluid. Questions remain regarding the magnitude of strain necessary to induce an osteocyte response, how the response propagates within the osteocyte network, and the timing involved in the initiation of bone resorption and/or formation on the bone surface. Mechanical loading in the form of shear stress is clearly involved not only in mechanosensation and transduction, but also in osteocyte viability. It remains to be determined if mechanical loading can also affect mineral homeostasis and mineralization, which are newly recognized functions of osteocytes.