Transgenic mice that express only the human renin gene were normotensive and yet exhibited a low bone mass, suggesting that osteoporosis occurs independently of the development of hypertension per se. Ex vivo cultures showed that angiotensin II (AngII) acted on osteoblasts and not directly on osteoclast precursor cells and increased osteoclastogenesis-supporting cytokines, RANKL and vascular endothelial growth factor (VEGF), thereby stimulating the formation of osteoclasts. Knockdown of AT2 receptor inhibited the AngII activity, whereas silencing of the AT1 receptor paradoxically enhanced it, suggesting a functional interaction between the two AngII receptors on the osteoblastic cell surface. Treatment of THM mice with an ACE inhibitor, enalapril, improved osteoporosis and hypertension, whereas treatment with losartan, an angiotensin receptor blocker specific for AT1, resulted in exacerbation of bone loss.

These results highlight the diverse roles of bone angiotensin receptors in the control of bone mass and turnover.

1. 1. Asaba Y et al. J Bone Miner Res. 2009;24:241–250.

To overcome these hurdles, the authors of a recent study [1] transduced CXCR4, a gene encoding the chemokine receptor largely responsible for stromal-derived factor-1 (SDF-1)-mediated BM homing, into murine MSC by adenovirus infection. A dose-dependent increase of CXCR4 surface expression with a parallel enhanced chemotaxis toward SDF-1 in these cells after virus infection was observed. Higher BM retention and homing of CXCR4-expressing MSCs were also found after they were transplanted by intramedullary and tail vein injections, respectively, into immunocompetent mice. Interestingly, a full recovery of bone mass and a partial restoration of bone formation in glucocorticoid-induced osteoporotic mice were observed 4 wk after a single intravenous infusion of one million CXCR4-expressing MSC cells. In the meantime, complete recovery of bone stiffness and strength in these animals was consistently detected only after a systemic transplantation of CXCR4 and Cbfa-1 co-transduced MSCs.

This is the first report to show unequivocally the feasibility of ameliorating glucocorticoid-induced osteoporosis by systemic transplantation of genetically manipulated MSCs.

1. Lien CY et al. J Bone Miner Res. 2009;24:837-848.

1. Leslie WD et al. J Bone Miner Res. 2009;24:353–360.

Logistic regression analysis adjusted for age, body mass index, and L-BMD showed that the presence of diabetes was an independent risk factor for prevalent vertebral fractures in women (OR = 1.86, P=0.019) and men (OR = 4.73, P<0.001). BMD at any site, however, was not significantly associated with the presence of prevalent vertebral fractures in diabetic patients, in contrast to the significant association in controls. Comparison of diabetic patients with and without vertebral fractures showed no significant differences in BMD values, bone markers, or diabetes status. Absolute L-, FN-, and R-BMD values for detecting prevalent vertebral fractures were higher in diabetic patients than controls, whereas their sensitivity and specificity were lower.

Type 2 diabetes patients may have an increased risk of vertebral fractures independent of BMD or diabetic complication status, suggesting that bone quality may define bone fragility in diabetes.

1. Yamamoto M et al. J Bone Miner Res. 2009;24:702–709.

This pathway is controlled by a phosphatase named PTEN which negatively regulates PI3K. Loss of PTEN in either embryonic stem cells or human cancer cell lines results in persistent activation of Akt, leading to increases in cell proliferation, survival, and migration.

To directly investigate the role of PTEN in osteoblasts in vivo, Liu et al. [1] disrupted the gene encoding PTEN in mice. Mice carrying an osteoblast-specific deletion of PTEN had normal body size but demonstrated progressive increases in bone volume and density throughout life. In vitro osteoblasts lacking PTEN differentiated more rapidly than controls and exhibited greatly reduced apoptosis in association with markedly increased levels of activated Akt and activation of signaling pathways downstream of Akt.

These findings support a critical role for this tumor-suppressor gene in regulating osteoblast lifespan and likely explain the skeletal abnormalities in patients carrying germ-line mutations of PTEN.

1. Liu X et al. Proc Natl Acad Sci USA. 2007;104: 2259-2264.

Five-year absolute risk of hip fracture was 3.9% in the Rotterdam Study and 3.1% in LASA, and 10-y absolute risk of hip fracture was 8.4% in the Rotterdam Study. Using Cox regression analysis, age (70–79 and 80+ versus <60–69) and four other risk factors were included in the risk profiles of hip fractures and fragility fractures: any prior fracture after age 50, body weight <64 kg, use of a walking aid as a proxy measure of serious immobility, and current smoking. Estimated 10-y absolute risk of hip fracture ranged from 1.4% in women, age 60–69 years, without any of these predictors to 29% in women, >80 y of age, having two or more positive risk factors.

A simple risk score can satisfactorily identify older women at high risk of osteoporotic fractures in general practice. Future studies are needed to validate this score.

1. Pluijm SMF et al. J Bone Miner Res. 2009;24:768–774.

Lamin A/C knockdown led to an inhibition of osteoblast proliferation by 26% and impaired osteoblast differentiation by 48% based on the formation of mineralized matrix. In mature osteoblasts, mRNA levels of two osteoblast markers, runx2 and osteocalcin, were decreased by lamin A/C knockdown by 44% and 78%, respectively. Furthermore, protein analysis showed that osteoblasts with diminished levels of lamin A/C also secreted less osteocalcin and expressed a lower alkaline phosphatase activity (−50%). Lamin A/C inhibition increased RANKL mRNA and protein levels, whereas osteoprotegerin (OPG) expression was decreased, resulting in an increased RANKL/OPG ratio and an enhanced ability to support osteoclastogenesis, as reflected by a 34% increase of TRACP+ multinucleated cells.

These data indicate that lamin A/C is essential for proper osteoblastogenesis. Moreover, lack of lamin A/C favors an osteoclastogenic milieu and contributes to enhanced osteoclastogenesis.

1. Rauner M et al. J Bone Miner Res. 2009;24:78–86.

Instead, the authors of this study [1] show here that Lrp5 inhibits expression of tryptophan hydroxylase 1 (Tph1), the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum. Accordingly, decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice, and gut- but not osteoblast-specific Lrp5 inactivation decreases bone formation in a β-catenin-independent manner. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents ovariectomy-induced bone loss. Serotonin acts on osteoblasts through the Htr1b receptor and CREB to inhibit their proliferation.

By identifying duodenum-derived serotonin as a hormone inhibiting bone formation in an Lrp5-dependent manner, this study broadens our understanding of bone remodeling, and suggests alternative avenues to increase bone mass.

1. Yadav VK et al. Cell. 2008;135: 825–837.

In a recent study [1], the authors show through mouse genetic studies that a deletion of the leptin receptor in neurons results in an increase in bone formation and bone resorption, resulting in a high bone mass as seen in leptin-deficient mice. In contrast, the same deletion in osteoblasts only does not influence bone remodeling. Furthermore, through the use of a mouse model of gain of function in leptin signaling harboring a mutation in the leptin receptor, they show that leptin signaling inhibits bone mass accrual by upregulating sympathetic activity independently of any change in appetite or energy expenditure.

This work establishes that in vivo leptin regulates bone mass accrual by acting through neuronal means and provides a direct demonstration that this function of leptin can occur independently of its regulation of energy metabolism.

1. Shia Y et al. Proc Natl Acad Sci USA. 2008;105:20529–20533.

In conclusion, the authors find that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification.

1. Schinke T et al. Nat Med. 2009;15:674-681.