More about FSH and bone: TNF comes into the game
Postmenopausal osteoporosis is traditionally attributed to declining estrogen levels. However, a recent study showed that follicle-stimulating hormone (FSH), the secretion of which is under estrogenic feedback, directly enhances osteoclast formation and function. The deletion of one of its subunits protects against bone loss despite severe hypogonadism. This finding suggests that elevated FSH contributes to the genesis of postmenopausal osteoporosis.
However, hypogonadal bone loss is accompanied by alterations in bone and bone marrow, notably enhanced bone formation, increased T lymphocyte production, and macrophage activation. The alterations in immune function have been attributed to an increase in TNFα production that is thought to arise from estrogen deficiency.
Pathological role of osteoclast costimulation in arthritis-induced bone loss
Osteoclasts, multinucleated cells of hematopoietic origin that degrade the bone matrix, are regulated by immunoregulatory molecules under both physiological and pathological conditions. Combined deficiency of Fc receptor common γsubunit (FcRγ) and DNAX-activation protein 12 (DAP12) results in a complete lack of osteoclasts. In addition to RANK, the receptor for RANK ligand (RANKL), the Ig-like receptors associated with FcRγ and DAP12 have been recognized as essential receptors for osteoclastogenesis. This observation established that Ig-like receptors function as osteoclast costimulatory receptors, which are crucial for bone homeostasis under physiological conditions.
BMP2 is mandatory for fracture healing
Bone repair is a key phenomenon to preserve skeleton stiffness and strength. It is not only important for fracture healing but also to repair bone microdamage resulting from mechanical constraints. The fist step in this regenerative procedure is the resorption of injured bone by efficient osteoclasts, followed by synthesis of new bone by osteoblasts.
Bone morphogenetic protein 2 (BMP2), synthesized by osteoblasts, accumulates in the extracellular matrix and was acknowledged as a factor promoting fracture repair in adult bone [1]. In order to evaluate the role of BMP2 during growth, Tsuji et al. [2] generated transgenic mice in which Bmp2 was inactivated in a limb-specific manner before the onset of skeletal development. These mice have few skeletal abnormalities at birth, suggesting that other BMPs present in the developing limb can compensate, at that stage, for the loss of BMP2.
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.
Regulation of cancer cell migration and bone metastasis by RANKL
Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain. It is now acknowledged that the microenvironment of the local host tissue actively participates in the propensity of certain cancers to metastasize to specific organs, and that bone provides an especially fertile ’soil’. In the case of breast cancers, the local chemokine milieu is now emerging as an explanation for why these tumors preferentially metastasize to certain organs. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behavior, other factors must exist that regulate the preferential metastasis of breast cancer cells.
 Download here the slide set presented by Prof. Friedlander, on Thursday, November 10th. |
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