Hypertension and osteoporosis are two major age-related disorders; however, the underlying molecular mechanism for this comorbidity is not known. The renin–angiotensin system (RAS) plays a central role in the control of blood pressure and has been an important target of antihypertensive drugs. Using a chimeric RAS model of transgenic THM (Tsukuba hypertensive mouse) expressing both the human renin and human angiotensinogen genes, the authors of a recent study [1] showed that activation of RAS induces high turnover osteoporosis with accelerated bone resorption.
Transplantation of gene-modified mesenchymal stem cells (MSCs) in animals for bone regeneration therapy has been evaluated extensively in recent years. However, increased endosteal bone formation by intravenous injection of MSCs ectopically expressing a foreign gene has not yet been shown. Aside from the clearance by lung and other tissues, the surface compositions of MSCs may not favor their bone marrow (BM) migration and engraftment.
Absolute 10-y fracture risk based on multiple factors is the preferred method for risk assessment. A simplified risk assessment system from sex, age, DXA, and two clinical risk factors (CRFs) prior fracture and systemic corticosteroid (CS) use has been used in Canada since 2005. This study [1] was undertaken to evaluate this system in the Canadian female population. A total of 16205 women >50 y of age at the time of baseline BMD (1998–2002) were identified in a database containing all clinical DXA test results for the Province of Manitoba, Canada. Basal 10-yr fracture risk from age and minimum T-score (lumbar spine, femur neck, trochanter, total hip) was categorized as low (<10%), moderate (10–20%), or high (>20%).
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Although patients with type 2 diabetes have an increased risk of hip fracture, risk of vertebral fracture (VF) and its association with BMD are still unclear. A recent study [1] examined Japanese type 2 diabetic patients (161 men >50 y and 137 postmenopausal women) and nondiabetic controls (76 and 622, respectively) by lateral spine radiography and DXA at the lumbar spine (L), femoral neck (FN), and radius (R).
The development and maintenance of the mammalian skeleton are controlled by actions of morphogens and growth factors on bone cells. Skeletal growth factors such as insulin-like growth factor-1 (IGF-1) affect bone formation and induce osteoblast proliferation and lifespan by activating antiapoptotic pathways, increasing cell proliferation, and influencing differentiation. A key control point in many antiapoptotic pathways is a kinase named phosphatidylinositol (PI) 3-kinase (PI3K), which is activated in response to various extracellular signals and leads to generation to lipidic second messengers. A key downstream target of this pathway is another kinase named Akt. When activated, Akt promotes cell growth and cell survival by regulating numerous downstream pathways.
A simple risk score for the assessment of absolute fracture risk in general practice
02/02/2010 in DiagnosisThe aim of this prospective study [1] was to develop a risk score, based on putative risk factors in current guidelines, which can be used to identify women at high risk of fractures in general practice. The study sample included 4157 women >60 y of age (mean ± SD: 74.1 ± 9.1 yr), with a median follow-up of 8.9 y of the Rotterdam Study (ERGO), and 762 women >65 y of age (mean ± SD: 76.0 ± 6.7.y), with a median follow-up of 6.0 y of the Longitudinal Aging Study Amsterdam (LASA). Potential risk factors were those proposed in risk scores of three recent guidelines on osteoporosis: age, family history of fractures, prior fracture, low body weight/body mass index (BMI), serious immobility, rheumatoid arthritis, current smoking, alcohol consumption >2 units daily, prevalent vertebral fracture, and systemic corticosteroid use.
Age-related osteoporosis is characterized by low bone mass, poor bone quality, and impaired osteoblastogenesis. Recently, the Hutchinson-Gilford progeria syndrome (HGPS), a disease of accelerated aging and premature osteoporosis, has been linked to mutations in the gene encoding for the nuclear lamina protein lamin A/C. Here [1], the authors tested the hypothesis that inhibition of lamin A/C in osteoblastic lineage cells impairs osteoblastogenesis and accelerates osteoclastogenesis. Lamin A/C was knockeddown with small interfering (si)RNA molecules in human bone marrow stromal cells (BMSCs) differentiating toward osteoblasts.
Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum
19/01/2010 in PhysiologyLoss- and gain-of-function mutations in the broadly expressed gene LDL receptor-related protein 5 (Lrp5) affect bone formation, causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor, osteoblast-specific disruption of β-catenin does not affect bone formation.
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.
The leptin regulation of bone remodeling, has been documented through studies of loss-of-function mutations of this hormone or of its receptor in mice and humans (see Osteoscoop Newsletter N°14, 15, 34, 37). However, unanswered questions remain. For instance, it has been assumed but not formally demonstrated that this regulation occurs through neuronal means. Likewise, it has not been possible until now to dissociate the influence leptin exerts on appetite and energy expenditure from this function.
Impaired gastric acidification negatively affects calcium homeostasis and bone mass
04/01/2010 in PathophysiologyActivation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. In a recent study [1], the authors show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in a gastrin receptor that affects acid secretion by parietal cells have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia.
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