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Peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]) is a nuclear receptor that functions as a master transcriptional regulator of adipocyte conversion. During PPAR[gamma] transactivation, multiple signaling pathways interact with one another, leading to the differentiation of both white and brown adipose tissue. Ligand activation of the PPAR[gamma]-RXR heterodimer complex also enhances insulin sensitivity, and this property has been heavily exploited to develop effective pharmacotherapies for the treatment of type 2 diabetes mellitus. PPAR[gamma] is also expressed in stem cells and plays a critical role in mesenchymal stromal cell differentiation and lineage determination events. The many facets of PPAR[gamma] activity within the bone marrow niche where adipocytes, osteoblasts, and hematopoietic cells reside make this molecule an attractive target for pharmacological investigation. Additional findings that osteoblasts can alter energy metabolism by influencing adiposity and insulin sensitivity, and observations of decreased bone turnover in diabetic subjects, underscore the contribution of the skeleton to systemic energy requirements. Studies into the role of PPAR[gamma] in skeletal acquisition and maintenance may lead to a better understanding of the molecular mechanisms governing stromal cell differentiation in the mesenchyme compartment and whether PPAR[gamma] activity can be manipulated to benefit skeletal remodeling events and energy metabolism. peroxisome proliferator-activated receptor-[gamma]; bone remodeling; energy metabolism doi: 10.1152/ajpendo.00157.2010.

In bone-remodeling studies, it is believed that the morphology of bone is affected by its internal mechanical loads. From the 1970s, high computing power enabled quantitative studies in the simulation of bone remodeling or bone adaptation. Among them, Huiskes et al. (1987, 'Adaptive Bone Remodeling Theory Applied to Prosthetic Design Analysis,' J. Biomech. Eng., 20, pp. 1135-1150) proposed a strain energy density based approach to bone remodeling and used the apparent density for the characterization of internal bone morphology. The fundamental idea was that bone density would increase when strain (or strain energy density) is higher than a certain value and bone resorption would occur when the strain (or strain energy density) quantities are lower than the threshold. Several advanced algorithms were developed based on these studies in an attempt to more accurately simulate physiological bone-remodeling processes. As another approach, topology optimization originally devised in structural optimization has been also used in the computational simulation of the bone-remodeling process. The topology optimization method systematically and iteratively distributes material in a design domain, determining an optimal structure that minimizes an objective function. In this paper, we compared two seemingly different approaches in different fields--the strain energy density based bone-remodeling algorithm (biomechanical approach) and the compliance based structural topology optimization method (mechanical approach)--in terms of mathematical formulations, numerical difficulties, and behavior of their numerical solutions. Two numerical case studies were conducted to demonstrate their similarity and difference, and then the solution convergences were discussed quantitatively. [DOI: 10.1115/1.3005202] Keywords: bone remodeling, bone adaptation, topology optimization, computational simulation

Drug targeting of adult stem cells has been proposed as a strategy for regenerative medicine, but very few drugs are known to target stem cell populations in vivo. Mesenchymal stem/progenitor cells (MSCs) are a multipotent population of cells that can differentiate into muscle, bone, fat, and other cell types in context-specific manners. Bortezomib (Bzb) is a clinically available proteasome inhibitor used in the treatment of multiple myeloma. Here, we show that Bzb induces MSCs to preferentially undergo osteoblastic differentiation, in part by modulation of the bone-specifying transcription factor runt-related transcription factor 2 (Runx-2) in mice. Mice implanted with MSCs showed increased ectopic ossicle and bone formation when recipients received low doses of Bzb. Furthermore, this treatment increased bone formation and rescued bone loss in a mouse model of osteoporosis. Thus, we show that a tissue-resident adult stem cell population in vivo can be pharmacologically modified to promote a regenerative function in adult animals., Introduction Multipotent bone marrow stromal cells capable of giving rise to osteoblasts, adipocytes, and chondrocytes (a population termed mesenchymal stem/progenitor cells [MSCs]) were originally described by Friedenstein in 1966 (1), [...]

Synthetic hydrogels have been molecularly engineered to mimic the invasive characteristics of native provisional extracellular matrices: a combination of integrin-binding sites and substrates for matrix metalloproteinases (MMP) was required to render the networks degradable and invasive by cells via cell-secreted MMPs. Degradation of gels was engineered starting from a characterization of the degradation kinetics ([k.sub.cat] and [K.sub.m]) of synthetic MMP substrates in the soluble form and after crosslinking into a 3D hydrogel network. Primary human fibroblasts were demonstrated to proteolytically invade these networks, a process that depended on MMP substrate activity, adhesion ligand concentration, and network crosslinking density. Gels used to deliver recombinant human bone morphogenetic protein-2 to the site of critical defects in rat cranium were completely infiltrated by cells and remodeled into bony tissue within 4 wk at a dose of 5 [micro]g per defect. Bone regeneration was also shown to depend on the proteolytic sensitivity of the matrices. These hydrogels may be useful in tissue engineering and cell biology as alternatives for naturally occurring extracellular matrix-derived materials such as fibrin or collagen. extracellular matrix | biomaterials | proteolytic degradation

We tested the hypothesis that fluid shear stress ([tau]) modifies the expression, function, and distribution of junctional proteins [connexin (Cx)43, Cx45, and zona occludens (ZO)-1] in cultured bone cells. Cell lines with osteoblastic (MC3T3-E1 cells) and osteocytic (MLO-Y4 cells) phenotypes were exposed to [tau]-values of 5 or 20 dyn/[cm.sup.2] for 1-3 h. Immunostaining indicated that at 5 dyn/[cm.sup.2], the distribution of Cx43, Cx45, and ZO-1 was moderately disrupted at cell membranes; at 20 dyn/[cm.sup.2], disruption was more severe. Intercellular coupling was significantly decreased at both shear stress levels. Western blots showed the downregulation of membrane-bound Cx43 and ZO-1 and the upregulation of cytosolic Cx43 and Cx45 at different levels of shear stress. Similarly, Northern blots revealed that expression of Cx43, Cx45, and ZO-1 was selectively up- and down-regulated in response to different shear stress levels. These results indicate that in cultured bone cells, fluid shear stress disrupts junctional communication, rearranges junctional proteins, and determines de novo synthesis of specific connexins to an extent that depends on the magnitude of the shear stress. Such disconnection from the bone cell network may provide part of the signal whereby the disconnected cells or the remaining network initiate focal bone remodeling. gap junctions; connexin; zona occludens-1; mechanotransduction; bone remodeling

Emerging medical technologies for effective and lasting repair of articular cartilage include delivery of cells or cell-seeded scaffolds to a defect site to initiate de novo tissue regeneration. Biocompatible scaffolds assist in providing a template for cell distribution and extracellular matrix (ECM) accumulation in a three-dimensional geometry. A major challenge in choosing an appropriate scaffold for cartilage repair is the identification of a material that can simultaneously stimulate high rates of cell division and high rates of cell synthesis of phenotypically specific ECM macromolecules until repair evolves into steady-state tissue maintenance. We have devised a self-assembling peptide hydrogel scaffold for cartilage repair and developed a method to encapsulate chondrocytes within the peptide hydrogel. During 4 weeks of culture in vitro, chondrocytes seeded within the peptide hydrogel retained their morphology and developed a cartilage-like ECM rich in proteoglycans and type II collagen, indicative of a stable chondrocyte phenotype. Time-dependent accumulation of this ECM was paralleled by increases in material stiffness, indicative of deposition of mechanically functional neo-tissue. Taken together, these results demonstrate the potential of a self-assembling peptide hydrogel as a scaffold for the synthesis and accumulation of a true cartilage-like ECM within a three-dimensional cell culture for cartilage tissue repair. three-dimensional cell culture | biological scaffold | regenerative medicine

Limited data in humans and animals indicate that excess vitamin A stimulates bone resorption and inhibits bone formation, effects that over time might lead to bone loss and fracture. Thus, it is possible that vitamin A supplementation is a currently unrecognized risk factor for the development of osteoporosis. To further evaluate this possibility, a prospective, randomized, single-blind study of vitamin A supplementation was conducted in 80 healthy men age 18-58 y. One half received 7576 [micro]g (25,000 iu) of retinol palmitate daily with their evening meal; the others took a placebo. Blood was collected from fasting subjects and serum prepared at baseline and after 2, 4 and 6 wk of supplementation. Serum bone specific alkaline phosphatase (BSAP) and N-Telopeptide of type I collagen (NTx) were measured at all time points. Serum osteocalcin (Oc) was measured at baseline and after 6 wk of supplementation. BSAP, NTx and Oc did not differ between the supplemented and placebo-treated groups over the course of the study. In conclusion, short-term vitamin A supplementation at this dosage in healthy men does not alter serum markers of skeletal turnover. Thus, it is unlikely that short-term administration of vitamin A would contribute to the development of osteoporosis. Whether long-term vitamin A supplementation might have adverse skeletal effects remains to be determined. Key Words: * vitamin A * retinol * osteoporosis * bone turnover * men

This article discusses the relationship between weight training, bone mass, and bone regeneration in the aged. An analysis of bone mineral density, cell proliferation, estrogen levels, and osteoporosis risk is presented.

Throughout life bone undergoes remodeling with removal of old bone (resorption) and replacement with new bone (formation). The bone remodeling cycle is the coupling between resorption and formation with the major stimulus to bone formation being prior bone resorption. Resorption is regulated by osteoclasts and formation by osteoblasts. Remodeling is most rapid during infancy with formation exceeding resorption and resultant positive skeletal balance. By age 6 or 7 this process slows down, only to accelerate briefly at puberty with formation again outstripping resorption for continued positive skeletal balance. From early adult life until the sixth decade remodeling is slow, resorption and formation are equal and there is no net gain or loss of bone. After age 50, for as yet unexplained reasons, resorption begins to exceed formation with net negative skeletal balance that continues negative (if left without intervention) for the rest of life. In women the decline in estrogen production at menopause stimulates bone resorption, increases the rate of remodeling but with resorption still exceeding formation. This results in a limited period (5-10 years) of accelerated bone loss in the early menopausal years. Many diseases/conditions/medications stimulate bone resorption and accelerate bone loss. These include hormone excess (cortisol, parathyroid, thyroid), hormone deficiency (estrogen, androgen, calcediol, calcitriol), malabsorption/malnutrition, and immobilization. The process of bone remodeling can be monitored biochemically and the levels of these biochemical markers of remodeling have been shown to predict rates of bone loss in women.

The B cell lymphoma 2 (Bcl-2) family member Bcl-xL is the major isoform produced following alternative splicing of the Bcl-x gene. Although its role as an antiapoptotic protein has been [...]