RANKL Inhibition: a novel strategy to decrease femoral head deformity after ischemic osteonecrosis
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.
PYK2 inhibition promotes bone formation: anabolic approach for the treatment of osteoporosis
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.
Mechanical loading, PPARγ, and osteoblastogenesis
The differentiation of multipotent stemcells of mesodermal origin results in the formation of adipocytes, chondrocytes, osteoblasts, and myoblasts. In humans, osteoporosis and age-related osteopenia are associated with an increase in marrow fat tissue and osteoblast numbers correlated negatively with the number of adipocytes. Osteoblastic differentiation is driven by runx2, and then characterized by the expression of alkaline phosphatase, osteocalcin, and eventually by the mineralization of the extracellular matrix.
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Overexpression of y-glutamyltransferase accelerates bone resorption and causes osteoporosis
Genetic studies in human patients as well as mutant mice have disclosed critical molecules involved in osteoclast development, including cytokines, intracellular signaling molecules, and nuclear transcription factors. Among these, the osteoclastogenic cytokines have received special attention, because they represent novel targets for the development of both diagnostic tools and antiresorptive drugs. For example RANKL, belonging to the TNF family, was identified as an essential cytokine for osteoclastogenesis, and mice deficient in RANKL were found to lack osteoclasts and to exhibit severe osteopetrosis. In an attempt to identify new cytokines that stimulate osteoclast differentiation, expression cloning was used and led to identify y-glutamyltransferase (GGT) as such a stimulator. Mice deficient in GGT exhibit growth retardation, cataracts, and severe osteoporosis and die at 10 ¿18 wk of age. Purified GGT is capable of inducing osteoclast formation in bone marrow cultures, which raises the possibility that its excess may also be involved in the bone and joint pathology characterized by enhanced osteoclastic bone resorption.
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Strontium ranelate reduces postmenopausal vertebral fracture risk independently of baseline risk factors
Osteoporosis and its consequent increase in fracture risk is a major health problem for postmenopausal women. Strontium ranelate is an orally active agent, which has been shown to both increase bone formation and reduce bone resorption and to improve bone architecture and bone resistance. In two large multinational studies of postmenopausal women with osteoporosis (the Spinal Osteoporosis Therapeutic Intervention (SOTI) study, and the Treatment of Peripheral Osteoporosis (TROPOS) study), treatment with strontium ranelate 2 g/day orally was shown to reduce significantly the risk of vertebral, nonvertebral, and hip fractures.
 Download here the slide set presented by Prof. Friedlander, on Thursday, March 29th. |
