Src family kinases (SFKs) are nonreceptor tyrosine kinases that are promiscuous in their impact on events such as growth, differentiation, cytoskeletal organization, and survival. One member of this family, c-Src kinase, is a rate-limiting activator of osteoclast function and Src inhibitors are therefore candidate antiosteoporosis drugs. By affecting M-CSF-induced signaling, c-Src is central to osteoclast activity, but not differentiation. The authors of a recent study [1] found that Lyn, another member of Src family kinases is, in contrast, a negative regulator of osteoclastic bone resorption.
Low-density lipoprotein receptor–related protein 5 (Lrp5) is a membrane protein acting as a coreceptor in canonical Wnt signaling. Lrp5 increases osteoblast proliferation, differentiation, and function. The purpose of a recent study [1] was to use Lrp5-deficient mice to evaluate the potential role of this gene in mediating the bone anabolic effects of parathyroid hormone (PTH).
Genetic studies in humans and mice have shown that the secreted protein sclerostin, synthesized by osteocytes, is a key negative regulator of bone formation, although the magnitude and extent of sclerostin’s role in the control of bone formation in the aging skeleton is still unclear. To study this unexplored area of sclerostin biology and to assess the pharmacologic effects of sclerostin inhibition, the authors of a recent study [1] used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl-AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis.
Estrogens are key hormones in bone remodeling. Estrogen deficiency in postmenopausal women frequently leads to osteoporosis, the most common skeletal disorder. Osteoporotic bone loss is the result of high bone turnover in which bone resorption outpaces bone formation. This imbalance can be ameliorated with bioavailable estrogens. Estrogens primarily act by regulating gene transcription via estrogen receptors (ERα, ERα). In mice, though ERα appears to be the major estrogen receptor, neither bone loss nor high bone turnover is detectable in ERα knock-out females. This unexpected maintenance of bone mass in female mutants is presumed to be due to unphysiologically elevated levels of other osteoprotective hormones, like androgens. Systemic defects in the hypothalamus caused by ER inactivation appear to impair the negative feedback system of hormone production. This leads to an excess in estrogen precursors, notably androgens. Thus, irrespective of the accumulating clinical and basic research data on the osteoprotective actions of estrogens, the molecular basis of this osteoprotection in females remains elusive. In this study [1], the authors report a critical role for ERα in mediating estrogen-dependent bone maintenance in female mice.
Bone modeling and remodeling are responsible for the construction of the skeleton during growth and its maintenance during adulthood. Bone remodeling involves the removal of a quantum of bone from a surface followed by the formation of new bone within the cavity created. Remodeling is carried out at spatially discrete foci by teams of cells that form the basic multicellular unit (BMU). The number of BMUs and the relative amounts of bone resorbed and formed within individual BMUs determine bone turnover. Assessment of remodeling balance and rate is achieved using static and dynamic histomorphometry. Estimation of remodeling balance requires measurement of the volume of bone formed (wall width) and resorbed (erosion depth) within individual BMUs. Measurement of erosion depth at completion of the resorptive phase of a remodeling cycle is problematic, imposing limitations on the accurate assessment of BMU balance. Remodeling rate is often expressed as the activation frequency, which represents the probability that a new remodeling cycle will be initiated at any point on the bone surface. Activation frequency represents the bone formation rate at surface level divided by the wall width. The histomorphometric derivation of activation frequency assumes that the remodeling rate is dependent on the duration of the remodeling cycle and the amount of bone formed in individual remodeling units. This implies that remodeling balance and remodeling rate are coregulated. A recent study [1] tested this assumption in normal human adult cancellous bone. Relationships between indices of bone formation at the basic multicellular unit (BMU) level (wall width and mineral apposition rate) and indices of remodeling rate (mineralizing perimeter and osteoid perimeter) were examined in iliac crest biopsies obtained from 57 healthy adults (24 men) 19 to 80 y of age.
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