Hypoxic Adipocytes Pattern Early Heterotopic Bone Formation

Texas A&M University - Galveston, Galveston, Texas, United States
American Journal Of Pathology (Impact Factor: 4.59). 03/2007; 170(2):620-32. DOI: 10.2353/ajpath.2007.060692
Source: PubMed


The factors contributing to heterotopic ossification, the formation of bone in abnormal soft-tissue locations, are beginning to emerge, but little is known about microenvironmental conditions promoting this often devastating disease. Using a murine model in which endochondral bone formation is triggered in muscle by bone morphogenetic protein 2 (BMP2), we studied changes near the site of injection of BMP2-expressing cells. As early as 24 hours later, brown adipocytes began accumulating in the lesional area. These cells stained positively for pimonidazole and therefore generated hypoxic stress within the target tissue, a prerequisite for the differentiation of stem cells to chondrocytes and subsequent heterotopic bone formation. We propose that aberrant expression of BMPs in soft tissue stimulates production of brown adipocytes, which drive the early steps of heterotopic endochondral ossification by lowering oxygen tension in adjacent tissue, creating the correct environment for chondrogenesis. Results in misty gray lean mutant mice not producing brown fat suggest that white adipocytes convert into fat-oxidizing cells when brown adipocytes are unavailable, providing a compensatory mechanism for generation of a hypoxic microenvironment. Manipulation of the transcriptional control of adipocyte fate in local soft-tissue environments may offer a means to prevent or treat development of bone in extraskeletal sites.

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Available from: Zbigniew Gugala
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    • "Thus, these two proteins represent factors which combine both, improvement in energy metabolism and positive regulation of bone mass. It has been reported that extraskeletal bone formation in either atherosclerotic vessels or in heterotopic bone is associated with a presence of adipocytes with brown phenotype suggesting their positive effect on tissue calcification [55], [56]. Although in the presented studies we did not observe bone anabolic activity of TEL, we cannot exclude that prolonged therapeutic use of TEL may be beneficial for bone by inducing bone anabolic activity in fat cells including marrow adipocytes. "
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    ABSTRACT: Peroxisome proliferator activated receptor gamma (PPARγ) controls both glucose metabolism and an allocation of marrow mesenchymal stem cells (MSCs) toward osteoblast and adipocyte lineages. Its activity is determined by interaction with a ligand which directs posttranscriptional modifications of PPARγ protein including dephosphorylation of Ser112 and Ser273, which results in acquiring of pro-adipocytic and insulin-sensitizing activities, respectively. PPARγ full agonist TZD rosiglitazone (ROSI) decreases phosphorylation of both Ser112 and Ser273 and its prolonged use causes bone loss in part due to diversion of MSCs differentiation from osteoblastic toward adipocytic lineage. Telmisartan (TEL), an anti-hypertensive drug from the class of angiotensin receptor blockers, also acts as a partial PPARγ agonist with insulin-sensitizing and a weak pro-adipocytic activity. TEL decreased S273pPPARγ and did not affect S112pPPARγ levels in a model of marrow MSC differentiation, U-33/γ2 cells. In contrast to ROSI, TEL did not affect osteoblast phenotype and actively blocked ROSI-induced anti-osteoblastic activity and dephosphorylation of S112pPPARγ. The effect of TEL on bone was tested side-by-side with ROSI. In contrast to ROSI, TEL administration did not affect bone mass and bone biomechanical properties measured by micro-indentation method and did not induce fat accumulation in bone, and it partially protected from ROSI-induced bone loss. In addition, TEL induced "browning" of epididymal white adipose tissue marked by increased expression of UCP1, FoxC2, Wnt10b and IGFBP2 and increased overall energy expenditure. These studies point to the complexity of mechanisms by which PPARγ acquires anti-osteoblastic and pro-adipocytic activities and suggest an importance of Ser112 phosphorylation status as being a part of the mechanism regulating this process. These studies showed that TEL acts as a full PPARγ agonist for insulin-sensitizing activity and as a partial agonist/partial antagonist for pro-adipocytic and anti-osteoblastic activities. They also suggest a relationship between PPARγ fat "browning" activity and a lack of anti-osteoblastic activity.
    Full-text · Article · May 2014 · PLoS ONE
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    • "Olmsted-Davis et al. [17] have demonstrated that adipocytes play a key role in establishing the hypoxic microenvironment necessary for ectopic bone formation to occur via endochondral ossification. The underlying mechanism is thought to be related with the hypoxia-inducible factor 1 (HIF-1) pathway. "
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    ABSTRACT: Heterotopic ossification (HO) consists of the formation of ectopic cartilage followed by endochondral bone, and is triggered by major surgeries, large wounds, and other conditions. Daily functions of HO patients can be hampered by the loss of normal posture, pain, inflammation, reduced mobility, formation of pressure ulcers, deep venous thrombosis, and other complications. Research so far revealed the molecular and cellular pathways leading HO formation, and proposed several possible mechanisms behind such pathways. Nonsteroidal anti-inflammatory drug (NSAID) regimens and localized low-dose irradiation are currently available as prophylaxis of HO formation. However, they are not always effective and do not target skeletogenic processes directly. New therapeutic modalities targeting pathological process of HO formation, such as bone morphogenetic proteins (BMP) inhibitors like Noggin, BMP type 1 receptor inhibitor, and nuclear retinoic acid receptor-gamma (RARγ) agonists are currently under investigation. In this review, we will summarize our current understanding of the pathology and molecular and cellular mechanisms of HO, especially endochondral heterotopic ossification, and then discuss its current and future therapies. We will also discuss the potential application of heterotopic ossification in the dental field.
    Full-text · Article · Jan 2013 · Japanese Dental Science Review
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    • "Studies in animal models also suggest that BAT may be involved in regulating osteoblastogenesis. Heterotrophic ossification modeled by the bone morphogenic protein-2 is known to induce the accumulation of brown adipocytes and subsequently trigger chondrocyte development and bone formation (56). Moreover, mice lacking functional BAT have very low bone mass, reduced osteoblast activity, and increased bone resorption (57). "
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    ABSTRACT: Brown adipose tissue (BAT) was thought to disappear after infancy. Recent studies finding BAT in patients undergoing positron emission tomography/computed tomography (PET/CT) have renewed the interest in deciphering the relevance of this tissue in humans. Available data suggests that BAT is more prevalent in children than in adults, and that its activation during adolescence is associated to significantly less gains in weight and adiposity. Data also shows that pediatric patients with metabolically-active BAT on PET/CT examinations have significantly greater muscle volume than patients with no identifiable BAT. Both the activity and the amount of BAT increase during puberty. The magnitude of the increase is higher in boys when compared to girls, and closely related to gains in muscle volume. Hence, concurrent with the great gains in skeletal muscle during infancy and puberty, all infants and adolescents accumulate large amounts of BAT. These observations are consistent with in vitro investigations suggesting close interactions between brown adipocytes, white adipocytes, and myocites. In this review, we discuss the potential role of this tissue in regulating weight and musculoskeletal development in children.Pediatric Research (2012); doi:10.1038/pr.2012.141.
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