Sclerostin, the protein product of the Sost gene, is a potent inhibitor of bone formation. Among bone cells, sclerostin is found nearly exclusively in the osteocytes, the cell type that historically has been implicated in sensing and initiating mechanical signaling. The recent discovery of the antagonistic effects of sclerostin on Lrp5 receptor signaling, a crucial mediator of skeletal mechanotransduction, provides a potential mechanism for the osteocytes to control mechanotransduction, by adjusting their sclerostin (Wnt inhibitory) signal output to modulate Wnt signaling in the effector cell population. We investigated the mechanoregulation of Sost and sclerostin under enhanced (ulnar loading) and reduced (hindlimb unloading) loading conditions. Sost transcripts and sclerostin protein levels were dramatically reduced by ulnar loading. Portions of the ulnar cortex receiving a greater strain stimulus were associated with a greater reduction in Sost staining intensity and sclerostin-positive osteocytes (revealed via in situ hybridization and immunohistochemistry, respectively) than were lower strain portions of the tissue. Hindlimb unloading yielded a significant increase in Sost expression in the tibia. Modulation of sclerostin levels appears to be a finely tuned mechanism by which osteocytes coordinate regional and local osteogenesis in response to increased mechanical stimulation, perhaps via releasing the local inhibition of Wnt/Lrp5 signaling.Low bone mass and poor bone structure are two major risk factors for osteoporotic fracture (1, 2). A simple yet effective means to enhance bone mass and architecture is through mechanical stimulation of the resident bone cell population (3, 4). Mechanical loading (e.g. exercise) improves bone mass and strength by stimulating the addition of new bone onto surfaces experiencing high strains, whereas surfaces that experience small strains largely remain quiescent. This phenomenon occurs both across the skeleton (limb bones adapt to locomotive loading, whereas nonbearing bones (e.g. skull) do not) and within a loaded bone (tension/compression surfaces undergo bone formation, whereas surfaces straddling the neutral bending axis do not). The cellular mechanisms involved in directing new bone formation to the high strain regions of a loaded bone are unclear, but elucidation of these mechanisms would provide an attractive target for pharmaceutical intervention aimed at mimicking the adaptive response to loading (5).Despite these gaps in our understanding, significant progress has been made in delineating some of the basic mechanisms of mechanotransduction in bone, in large part because of the creation of genetically engineered mice. A key finding in this arena is the requirement for Wnt signaling through Lrp5 (the low density lipoprotein receptor-related protein 5) in mechanically induced bone formation. We reported recently that mice engineered with a loss-of-function mutation in Lrp5 recapitulate the low bone mass phenotype observed in humans with inactivating mutations of LRP...
Bone is a dynamic tissue that is constantly renewed. The cell populations that participate in this process--the osteoblasts and osteoclasts--are derived from different progenitor pools that are under distinct molecular control mechanisms. Together, these cells form temporary anatomical structures, called basic multicellular units, that execute bone remodeling. A number of stimuli affect bone turnover, including hormones, cytokines, and mechanical stimuli. All of these factors affect the amount and quality of the tissue produced. Mechanical loading is a particularly potent stimulus for bone cells, which improves bone strength and inhibits bone loss with age. Like other materials, bone accumulates damage from loading, but, unlike engineering materials, bone is capable of self-repair. The molecular mechanisms by which bone adapts to loading and repairs damage are starting to become clear. Many of these processes have implications for bone health, disease, and the feasibility of living in weightless environments (e.g., spaceflight).
Introduction A subpopulation (CD44 + /CD24 -) of breast cancer cells has been reported to have stem/progenitor cell properties. The aim of this study was to investigate whether this subpopulation of cancer cells has the unique ability to invade, home, and proliferate at sites of metastasis.
Mechanotransduction plays a crucial role in the physiology of many tissues including bone. Mechanical loading can inhibit bone resorption and increase bone formation in vivo. In bone, the process of mechanotransduction can be divided into four distinct steps: (1) mechanocoupling, (2) biochemical coupling, (3) transmission of signal, and (4) effector cell response. In mechanocoupling, mechanical loads in vivo cause deformations in bone that stretch bone cells within and lining the bone matrix and create fluid movement within the canaliculae of bone. Dynamic loading, which is associated with extracellular fluid flow and the creation of streaming potentials within bone, is most effective for stimulating new bone formation in vivo. Bone cells in vitro are stimulated to produce second messengers when exposed to fluid flow or mechanical stretch. In biochemical coupling, the possible mechanisms for the coupling of cell-level mechanical signals into intracellular biochemical signals include force transduction through the integrin-cytoskeleton-nuclear matrix structure, stretch-activated cation channels within the cell membrane, G protein-dependent pathways, and linkage between the cytoskeleton and the phospholipase C or phospholipase A pathways. The tight interaction of each of these pathways would suggest that the entire cell is a mechanosensor and there are many different pathways available for the transduction of a mechanical signal. In the transmission of signal, osteoblasts, osteocytes, and bone lining cells may act as sensors of mechanical signals and may communicate the signal through cell processes connected by gap junctions. These cells also produce paracrine factors that may signal osteoprogenitors to differentiate into osteoblasts and attach to the bone surface. Insulin-like growth factors and prostaglandins are possible candidates for intermediaries in signal transduction. In the effector cell response, the effects of mechanical loading are dependent upon the magnitude, duration, and rate of the applied load. Longer duration, lower amplitude loading has the same effect on bone formation as loads with short duration and high amplitude. Loading must be cyclic to stimulate new bone formation. Aging greatly reduces the osteogenic effects of mechanical loading in vivo. Also, some hormones may interact with local mechanical signals to change the sensitivity of the sensor or effector cells to mechanical load.
Exercise during growth results in biologically important increases in bone mineral content (BMC). The aim of this study was to determine whether the effects of loading were site specific and depended on the maturational stage of the region. BMC and humeral dimensions were determined using DXA and magnetic resonance imaging (MRI) of the loaded and nonloaded arms in 47 competitive female tennis players aged 8 -17 years. Periosteal (external) cross-sectional area (CSA), cortical area, medullary area, and the polar second moments of area (I P , mm 4 ) were calculated at the mid and distal sites in the loaded and nonloaded arms. BMC and I P of the humerus were 11-14% greater in the loaded arm than in the nonloaded arm in prepubertal players and did not increase further in peri-or postpubertal players despite longer duration of loading (both, p < 0.01). The higher BMC was the result of a 7-11% greater cortical area in the prepubertal players due to greater periosteal than medullary expansion at the midhumerus and a greater periosteal expansion alone at the distal humerus. Loading late in puberty resulted in medullary contraction. Growth and the effects of loading are region and surface specific, with periosteal apposition before puberty accounting for the increase in the bone's resistance to torsion and endocortical contraction contributing late in puberty conferring little increase in resistance to torsion. Increasing the bone's resistance to torsion is achieved by modifying bone shape and mass, not necessarily bone density. (J Bone Miner Res 2002;17:2274 -2280)
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