Osteoscoop

Physiological function of the renin-angiotensin system in bone remodeling

Osteoscoop — Tue, 31 Jan 2012 14:13:47 +0000

Vascular and bone biology have many features and regulatory mechanisms in common; both systems are subject to tissue remodeling in response to various physiologic and pathologic stimuli. As a result, osteoporosis and vascular disease often coincide in the elderly, with the most common associations being elevated blood pressure, calcification of the vascular wall, and reduced bone mineral density.

The renin-angiotensin system (RAS) is a central regulator of blood pressure as well as fluid and electrolyte balance. In the classic endocrine cascade, renin produced by the juxtaglomerular apparatus of the kidney cleaves liver-produced angiotensinogen to angiotensin I, which is then cleaved by angiotensin-converting enzyme (ACE) to generate the biologically active angiotensin II.

The aim of this study was to determine whether the RAS had any physiologic function in bone metabolism. The authors [1] studied the effect of the absence of angiotensin receptor AT1a, using micro-CT scanning, histomorphometric and biochemical techniques.

They showed that the absence of this receptor was associated with an increased trabecular bone volume, along with increased trabecular number and connectivity. Furthermore, histomorphometric analysis showed that activity of bone formation as well as bone resorption was increased. However, the differentiation capacity of osteoclasts and osteoblasts seems to be preserved in the absence of angiotensin AT1a receptors.
Quantitative RT-PCR using mRNAs isolated from the tibia and femur revealed that the receptor activator of NF-B ligand (RANKL)/ostoprotegerin (OPG) ratio was increased, favoring bone resorption. On the other hand, in osteocytes, production of SOST, coding for sclerostin, was decreased. This change may have accounted for the increased bone formation. These knockout mice displayed a lean phenotype with reduced serum leptin level and maintained high bone mass with advancing age. Females were also protected from bone loss after ovariectomy.
Altogether, these data suggest that RAS has a physiologic function in bone remodeling. This study highlights the role of angiotensin II as a negative regulator of bone turnover and bone mass through AT1a receptors.

Kaneko K et al. J Bone Miner Res. 2011;26:2959-2966.

Adipocyte-secreted factors and higher bone mass in obese people

Osteoscoop — Tue, 24 Jan 2012 14:56:07 +0000

Several studies have reported controversial results about the positive correlation between the body fat mass and bone mineral density. It remains unclear whether some adipocyte-secreted factors can act on bone metabolism, directly on osteoblasts, to favor bone formation or osteoclasts, which control bone resorption. The authors of this study [1] investigated the effect of fat cell secreted molecules on proliferation and differentiation of preosteoblasts.

They showed that fat cell secretion factors increased proliferation of murine preosteoblast cells by almost 3-fold. This proliferation was reduced by inhibiting FGFR1, the receptor of FGF. Accordingly, the authors evidenced that human adipocytes secreted bFGF. This molecule alone is sufficient to induce preosteoblast proliferation. When preosteoblasts were stimulated to proliferate by adipocyte-secreted factors, the OPG/RANKL ratio increased 9-fold in a PI3K-dependant manner. OPG (osteoprotegerin) is a well-known inhibitor of osteoclast differentiation and bone resorption. On the other hand, RANKL promotes osteoclast differentiation. Moreover, stimulated pre-osteoblasts inhibited the formation of mature osteoclasts.

In conclusion, human adipocytes secrete factors that directly act on preosteoblasts and alter their crosstalk with osteoclasts. This study highlights the effects of adipocytes on bone metabolism and argues in favor of the positive relationship between body fat mass and bone mineral density. It could explain the higher bone mass in obese people.

Kühn MC et al. Mol Cell Endocrinol. 2011; Doi :10.1016/j.mce.2011.10.018.

Optimal monitoring time interval between DXA measures in children

Osteoscoop — Tue, 17 Jan 2012 15:07:41 +0000

The monitoring time interval (MTI) is the expected time in years necessary to detect a significant change between two measures that exceeds the measurement error. The aim of this paper [1] was to determine MTI values for dual X-ray absorptiometry (DXA) scans in normal children according to age, sex, and skeletal sites.

2014 children were enrolled in this study with seven annual bone mineral density measurements of spine, hip, 1/3 radius, femoral neck and total body less head (TBLH) along with bone mineral content of spine and TBLH from 2002 to 2010. DXA precision errors were obtained with a subgroup of 155 children that had duplicate scans.

The MTI values were significantly under 1 year for the TBLH and spine BMD, for boys <17 years and girls <15 years. The hip and one third radius MTIs were around 1 year in these groups.

MTI minimum values were around 3 months during the peak growth years. On the contrary, MTI values in the late adolescence for all regions became longer and nonsensical as each region neared the age of peak bone density.

The authors conclude that DXA precision errors and annual rates of change for BMD and BMC in children vary with region of interest, age, and sex. Resulting MTI measures are similar for boys and girls below puberty and provide useful guidelines for scanning intervals. For older adolescents, some other clinical criteria must be used to determine DXA scanning intervals.

Shepherd JA et al. J Bone Miner Res. 2011;26:2745-2752.

Inpp4b as a regulator of bone mass

Osteoscoop — Tue, 10 Jan 2012 15:16:26 +0000

Osteoclasts are the major cell type involved in bone resorption. Unbalanced increase of osteoclasts activity decreases bone mass and favors osteoporosis. The authors of this study [1] identified a regulator of osteoclastogenesis, inositol polyphosphate 4-phosphatase type 2 α (Inpp4bα), a member of the PI3 kinase signaling pathway.

This phosphatase was expressed from early osteoclast differentiation to activation stage. Ex vivo expression of Inpp4bα repressed osteoclast differentiation, whereas inactive Inpp4bα mutant increased shape, number and cell differentiation rate. Inpp4bα affected intracellular calcium level that controlled NFATc1 nuclear localization and led to an increase in the expression of osteoclast genes differentiation. In vivo, mice deficient in Inpp4b showed an increased osteoclast differentiation resulting in a decreased bone mass and osteoporosis. The authors identified human INPP4B as a potential important locus for osteoporosis.

This study highlights the role of Inpp4b as a major modulator of osteoclastogenesis which could be involved in bone mineral density variability in mice and humans.

Ferron M et al. Cell Metab. 2011;14:466-477.

Gfi1: a new therapeutic target for multiple myeloma bone disease

Osteoscoop — Tue, 03 Jan 2012 16:28:46 +0000

Inhibition of osteoblast differentiation characterizes multiple myeloma (MM) bone disease and persists even when patients are in long-term remission. The authors of this study [1] developed a murine multiple myeloma model in which the bone marrow stromal cells remained unresponsive to osteoblast differentiation, inhibiting signals after removal of MM cells.

They found that bone marrow stromal cells, in MM-bearing mice and in MM patients, had an increased expression of the transcriptional repressor Gfi1. This factor repressed the transcription factor Runx2 which is critical for osteoblast differentiation. Increased Gfi1 level and Runx2 repression were blocked by anti-TNF-α and IL-7 antibodies. These cytokines are produced massively by MM cells. Importantly, bone marrow stromal cells isolated from Gfi1-/- mice were resistant to MM-induced osteoblastogenesis suppression. Furthermore, Gfi1 knockdown by specific siRNA in bone marrow stromal cells from MM patients restored Runx2 level and osteoblastogenesis markers.

These data highlight the important role of Gfi1 cellular amount in prolonged MM-induced osteoblast suppression and identifies Gfi1 as a new potential therapeutic target for MM bone disease.

D’Souza S et al. Blood. 2011; doi:10.1182/blood-2011-04-346775.

Sympathetic control of bone mass is regulated by osteopontin

Osteoscoop — Tue, 27 Dec 2011 08:46:40 +0000

Activation of the sympathetic nervous system is known to reduce bone mass through mechanisms that remain unclear. Using cell-based studies and murine genetics, the authors [1] showed that osteopontin (OPN) is required for the sympathetic activity on bone metabolism.

Osteopontin is a cytokine and one of the major members of noncollagenous extracellular matrix proteins of bone. In this work the authors found that the stimulation of sympathetic tone by isoproterenol increased the level of OPN expression in bone, increased osteoclast activity, and reduced osteoblast activity and bone mass. In knockout mice deprived of OPN, isoproterenol had no inhibitory effect on bone mass, suggesting that OPN was directly involved in this pathway. Furthermore, OPN was required to induce the expression of osteoclastic genes and to repress the expression of osteoblastic genes. At the cellular level, this study suggested that osteoblast intracellular OPN modulated the capacity of the b2 adrenergic receptors to generate cyclic AMP with a corresponding modulation of cyclic AMP responsive element binding (CREB) phosphorylation. This event reduced subsequent transcription, occurring inside the osteoblast.

This study highlights the role of osteopontin and the role of the sympathetic nervous system in the regulation of bone mass through the modulation of the b2 adrenergic receptor-cyclic AMP signaling system.

Nagao M et al. Proc Natl Acad Sci USA. 2011;108:17767-17772.

Bone microarchitecture assessed by TBS predicts osteoporotic fracture independently of bone density

Osteoscoop — Tue, 20 Dec 2011 12:34:28 +0000

The measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) is the ‘‘gold standard’’ for diagnosing osteoporosis but does not directly reflect deterioration in bone microarchitecture. Trabecular bone score (TBS) is a novel measurement of the trabecular bone microarchitecture quantifying local variations in gray level. Like BMD, TBS can be measured from DXA scans. This new texture measurement uses experimental variograms of 2D projection images to differentiate between 3D microarchitectures that exhibit the same BMD but different trabecular characteristics. The authors of this study [1] aimed at evaluating the ability of this parameter to predict future clinical osteoporotic fracture.

Using hip and spine DXA scans of 29 407 postmenopausal women, associated with their medical records, the authors showed that, like BMD, a lower TBS score was associated with major osteoporotic, spine, or hip fractures. Using the number of osteoporotic fractures that occurred after the DXA scan analysis, the authors showed that spine TBS and BMD predicted fractures equally well. The combination of these two parameters allowed better prediction than either measurement alone.

Since spine TBS provides new information independent of spine BMD or hip BMD, combining trabecular bone microarchitecture and bone mineral density variations would improve further fracture prediction in postmenopausal women.

Hans D et al. J Bone Miner Res. 2011;26:2762-2769.

Sirt1 is a regulator of bone mass and a repressor of Sost encoding Sclerostin

Osteoscoop — Tue, 13 Dec 2011 10:30:43 +0000

Sirtuin 1 (Sirt1) is a member of the sirtuin family. The sirtuins are a family of evolutionarily highly conserved protein deacetylases that were found to regulate the lifespan in lower species and key cellular and metabolic functions in mammals. Sirt1 is a deacetylase that plays an important role in metabolism and in age-associated diseases.

The authors of this study [1] aimed at understanding the possible role of Sirt1 in skeletal homeostasis, which is presently unknown. They constructed a haplo-insufficient Sirt+/- mouse and showed that a reduced Sirt1 protein level decreased bone mass in females. This decrease of bone mass was due to a reduced bone formation rate consecutive to low osteoblastic activity. Importantly, Sost, the gene coding for sclerostin, an inhibitor of bone formation, was upregulated in Sirt+/- mice. Using chromatin immunoprecipitation, the authors showed that Sirt1 acted directly on Sost promoter to negatively regulate gene expression by deacetylating histone 3 which was important in controlling gene transcription. Low levels of Sirt1 increased sclerostin level. Sost downregulation restored osteoblastic activity markers.

These findings highlight the role of Sirt1 as a bone mass regulator and repressor of sclerostin and as a possible important actor to regulate bone mass in physiological and pathophysiological states.

Cohen-Kfir E et al. Endocrinology. 2011; 152: doi:10.1210/en.2011-1128.

Evidence for osteocyte regulation of bone homeostasis through RANKL expression

Osteoscoop — Mon, 05 Dec 2011 16:34:16 +0000

Agrowing number of evidence suggests that osteocytes orchestrate bone homeostasis by regulating the number and activity of bone-forming osteoblasts and bone-resorbing osteoclasts.
Using cell fractionation and purification techniques, the authors of this study [1] demonstrated that osteocytes produced larger amounts of RANKL mRNA than osteoblasts. RANKL is the key component involved in osteoclast differentiation. Osteocytes also exhibited a greater capacity to induce osteoclastogenesis than osteoblasts in vitro. Constructed transgenic mice, with osteocytes specifically lacking the ability to express RANKL, showed a decrease capacity to stimulate osteoclastogenesis. After birth, these mice presented with a severe osteopetrotic phenotype, indicating that osteocytes are the major source of RANKL in bone remodeling during mice growth in vivo.
The key role of osteocyte expression of RANKL has shed light on an unexpected network among bone cells and may provide a molecular basis for future therapeutic approach to bone diseases.

Nakashima T et al. Nat Med. 2011; 17: 1231-34

Is greater lumbar vertebral BMD associated with more disk degeneration ?

Osteoscoop — Tue, 29 Nov 2011 10:48:51 +0000

Although numerous studies have shown an association of osteoarthritis with greater bone mineral density (BMD) in peripheral extremities, the relationship between vertebral BMD and disk degeneration remains controversial, possibly due to the inadequacies of BMD and disk degeneration measures.

The authors [1] studied 137 cadaveric lumbar vertebrae and 209 corresponding intervertebral disks, using micro-computed tomography (mCT) to measure vertebral BMD, and discography to assess disk degeneration. To increase accuracy of BMD measures, they quantified BMD for the whole vertebra, for the vertebra without posterior elements (vertebral body) and for the vertebral body without osteophytes and endplates.

No significant association was found between whole vertebra BMD and adjacent disk degeneration. However, when posterior elements were excluded, there was a significant association between greater vertebral BMD and more severe degeneration of the adjacent cranial disk. Exclusion of osteophytes and endplates did not change this association.

Thus this study may lead to novel insights into the interaction between vertebra and disk and the etiology of lumbar disk degeneration.

Wang Y et al. J Bone Miner Res.. 2011; 26:2785-91