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Ota K.,Endocrine Research Unit and Robert and Arlene Kogod Center on Aging | Quint P.,Endocrine Research Unit and Robert and Arlene Kogod Center on Aging | Weivoda M.M.,Endocrine Research Unit and Robert and Arlene Kogod Center on Aging | Ruan M.,Endocrine Research Unit and Robert and Arlene Kogod Center on Aging | And 5 more authors.
Bone | Year: 2013

The processes of bone resorption and bone formation are tightly coupled in young adults, which is crucial to maintenance of bone integrity. We have documented that osteoclasts secrete chemotactic agents to recruit osteoblast lineage cells, contributing to coupling. Bone formation subsequent to bone resorption becomes uncoupled with aging, resulting in significant bone loss. During bone resorption, osteoclasts release and activate transforming growth factor beta 1 (TGF-β1) from the bone matrix; thus, elevated bone resorption increases the level of active TGF-β in the local environment during aging. In this study, we examined the influences of TGF-β1 on the ability of osteoclasts to recruit osteoblasts. TGF-β1 increased osteoclast expression of the chemokine CXCL16 to promote osteoblast migration. TGF-β1 also directly stimulated osteoblast migration; however, this direct response was blocked by conditioned medium from TGF-β1-treated osteoclasts due to the presence of leukemia inhibitory factor (LIF) in the medium. CXCL16 and LIF expression was dependent on TGF-β1 activation of Smad2 and Smad3. These results establish that TGF-β1 induces CXCL16 and LIF production in osteoclasts, which modulate recruitment of osteoblasts to restore the bone lost during the resorptive phase of bone turnover. © 2013 The Authors.


PubMed | Endocrine Research Unit and Robert and Arlene Kogod Center on Aging
Type: Journal Article | Journal: Journal of cellular biochemistry | Year: 2013

Osteoclast-mediated bone resorption precedes osteoblast-mediated bone formation through early adulthood, but formation fails to keep pace with resorption during aging. We previously identified several factors produced by osteoclasts that promote bone formation. In this study, we determined if osteoclast-produced factors contribute to the impaired bone formation with aging. We previously found that mice between the ages of 18 and 22 months develop age-related bone loss. Bone marrow-derived pre-osteoclasts were isolated from 6-week, 12-month, and 18- to 24-month-old mice and differentiated into osteoclasts in vitro. Conditioned media were collected and compared for osteoblast mineralization support. Conditioned medium from osteoclasts from all ages was able to support mineralization of bone marrow stromal cells. Concentrating the conditioned medium from 6-week-old and 12-month-old mouse marrow cells-derived osteoclasts enhanced mineralization support whereas concentrated conditioned medium from 18- to 24-month-old mouse marrow-derived osteoclasts repressed mineralization compared to base medium. This observation suggests that an inhibitor of mineralization was secreted by aged murine osteoclasts. Gene and protein analysis revealed that the Wnt antagonist sclerostin was significantly elevated in the conditioned media from 24-month-old mouse cells compared to 6-week-old mouse cells. Antibodies directed to sclerostin neutralized the influences of the aged mouse cell concentrated conditioned media on mineralization. Sclerostin is primarily produced by osteocytes in young animals. This study demonstrates that osteoclasts from aged mice also produce sclerostin in quantities that may contribute to the age-related impairment in bone formation.


PubMed | Endocrine Research Unit and Robert and Arlene Kogod Center on Aging
Type: Journal Article | Journal: Endocrinology | Year: 2011

In the bone marrow cavity, adipocyte numbers increase, whereas osteoblast progenitor numbers decrease with aging. Because adipocytes and osteoblasts share a common progenitor, it is possible that this shift is due to an increase in adipocyte-lineage cells at the expense of osteoblast-lineage commitment. Estrogens inhibit adipocyte differentiation, and in both men and women, circulating estrogens correlate with bone loss with aging. In bone cells, estrogens stimulate expression of TGF- and suppress mesenchymal cell adipogenesis. Using a tripotential mesenchymal cell line, we have examined whether estradiol suppression of adipocyte differentiation is due to stimulation of TGF- and the mechanism by which TGF- suppresses adipogenesis. We observed that estradiol-mediated suppression of adipogenic gene expression required at least 48 h treatment. TGF- expression increased within 24 h of estradiol treatment, and TGF- inhibition reversed estradiol influences on adipogenesis and adipocyte gene expression. Connective tissue growth factor (CTGF) mediates TGF- suppression of adipogenesis in mouse 3T3-L1 cells. CTGF expression was induced within 24 h of TGF- treatment, whereas estradiol-mediated induction required 48 h treatment. Moreover, estradiol-mediated induction of CTGF was abrogated by TGF- inhibition. These data support that estradiol effects on adipogenesis involves TGF- induction, which then induces CTGF to suppress adipogenesis.

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Loading Endocrine Research Unit and Robert and Arlene Kogod Center on Aging collaborators