Osteoporosis-related fractures constitute a major public health concern in women and men, and the fracture risk is highly dependent on bone mineral density (BMD). Although it is well established that obesity is a major risk factor for several common and severe diseases, the link between obesity and osteoporosis is less clear. A large body of evidence supports the notion that body weight is positively associated with areal BMD (aBMD) in both sexes and at all ages throughout adulthood, and negatively associated with fracture incidence. However, it remains a controversy whether it is lean mass or adipose tissue that mediates the bone stimulatory effect exerted by weight.

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The increase in bone resorption caused by estrogen deficiency is the major cause of postmenopausal bone loss and osteoporosis. This increase in bone resorption is thought to be mediated largely by changes in cytokine levels in the bone microenvironment. Based mainly on studies in ovariectomized rodents, proinflammatory cytokines, including TNF-α and interleukin (IL)-1β have been suggested as mediators. However, their roles are unclear in humans, whose immune system differs markedly from that of rodents.

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Osteopetrosis is a genetically and clinically heterogeneous bone disorder characterized by a reduction in bone resorption and a generalized net accumulation of skeletal mass. The causative genes identified so far all play a role in acidification of the resorption lacuna, and loss-of-function mutations in these genes severely affect mature osteoclast function. The CA2 (carbonic anhydrase 2) gene produces the protons necessary for acidification of the resorption lacuna, the extracellular compartment between the bone tissue and the osteoclast where bone resorption occurs. The α3 subunit of the H+ ATPase is involved in the transportation of these protons through the ruffled border into the resorption lacuna, while chloride channel 7 (ClC-7) translocates chloride ions to maintain electroneutrality.

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Interaction of RANKL and its cognate receptor, RANK, has been shown to play a critical role in osteoclast formation, activation, and survival. Endogenous osteoprotegerin (OPG) has been elucidated as a soluble decoy receptor for RANKL and serves as the key physiologic regulator of osteoclastic bone resorption. Binding of OPG to RANKL prevents RANK¿RANKL interaction and effectively inhibits bone resorption. The therapeutic potential of RANKL inhibitors, such as exogenous OPG (OPG-Fc), to decrease bone resorption has to be evaluated in various pathological situations. The hypothesis that inhibiting RANKL with OPG-Fc will prevent pathologic bone resorption and preserve the structural integrity of the femoral head after ischemic osteonecrosis was tested by Kim et al. [1] in piglets.

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Proline-rich tyrosine kinase 2 (PYK2) is a non-receptor tyrosine kinase, expressed in both bone-forming osteoblasts and bone-resorbing osteoclasts. Up to now, the skeletal phenotype of PYK2-/- mice has not been described. In vitro studies pointed to a positive role for PYK2 in osteoclast maturation and bone resorption. PYK2 localizes to the podosomes of osteoclasts. PYK2 might have a positive role in osteoblasts as well. Treatment of osteoblast cells with fluoroaluminate led to increased PYK2 activity and was associated with increased cell attachment and spreading, and PYK2 activity was stimulated in osteoblast-like cells after mechanical strain. In a recent study [1], the function of PYK2 in bone was elucidated using PYK2-/- mice and derived bone marrow cultures, as well as molecular and pharmacological inhibitors of this enzyme.

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