Liver-derived IGF-I regulates cortical bone mass but is dispensable for the osteogenic response to mechanical loading in female mice

Low circulating IGF-I is associated with increased fracture risk. Conditional depletion of IGF-I produced in osteoblasts or osteocytes inhibits the bone anabolic effect of mechanical loading. Here, we determined the role of endocrine IGF-I for the osteogenic response to mechanical loading in young adult and old female mice with adult, liver-specific IGF-I inactivation (LI-IGF-I−/− mice, serum IGF-I reduced by ≈70%) and control mice. The right tibia was subjected to short periods of axial cyclic compressive loading three times/wk for 2 wk, and measurements were performed using microcomputed tomography and mechanical testing by three-point bending. In the nonloaded left tibia, the LI-IGF-I−/− mice had lower cortical bone area and increased cortical porosity, resulting in reduced bone mechanical strength compared with the controls. Mechanical loading induced a similar response in LI-IGF-I−/− and control mice in terms of cortical bone area and trabecular bone volume fraction. In fact, mechanical loading produced a more marked increase in cortical bone mechanical strength, which was associated with a less marked increase in cortical porosity, in the LI-IGF-I−/− mice compared with the control mice. In conclusion, liver-derived IGF-I regulates cortical bone mass, cortical porosity, and mechanical strength under normal (nonloaded) conditions. However, despite an ∼70% reduction in circulating IGF-I, the osteogenic response to mechanical loading was not attenuated in the LI-IGF-I−/− mice.

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Bisphosphonate Maintains Parathyroid Hormone (1-34)-Induced Cortical Bone Mass and Mechanical Strength in Old Rats

Calcified Tissue International ◽

10.1007/s002239900438 ◽

1998 ◽

Vol 62 (4) ◽

pp. 316-322 ◽

Cited By ~ 16

Author(s):

C. Ejersted ◽

H. Oxlund ◽

T. T. Andreassen

Keyword(s):

Parathyroid Hormone ◽

Bone Mass ◽

Mechanical Strength ◽

Cortical Bone ◽

Old Rats ◽

Cortical Bone Mass

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Female Mice Lacking Estrogen Receptor-α in Hypothalamic Proopiomelanocortin (POMC) Neurons Display Enhanced Estrogenic Response on Cortical Bone Mass

Endocrinology ◽

10.1210/en.2016-1181 ◽

2016 ◽

Vol 157 (8) ◽

pp. 3242-3252 ◽

Cited By ~ 17

Author(s):

H. H. Farman ◽

S. H. Windahl ◽

L. Westberg ◽

H. Isaksson ◽

E. Egecioglu ◽

...

Keyword(s):

Estrogen Receptor ◽

Bone Mass ◽

Mechanical Strength ◽

Cortical Bone ◽

Volume Fraction ◽

Bone Thickness ◽

Female Mice ◽

Cortical Bone Thickness ◽

Cortical Bone Mass ◽

Estrogenic Responses

Estrogens are important regulators of bone mass and their effects are mainly mediated via estrogen receptor (ER)α. Central ERα exerts an inhibitory role on bone mass. ERα is highly expressed in the arcuate (ARC) and the ventromedial (VMN) nuclei in the hypothalamus. To test whether ERα in proopiomelanocortin (POMC) neurons, located in ARC, is involved in the regulation of bone mass, we used mice lacking ERα expression specifically in POMC neurons (POMC-ERα−/−). Female POMC-ERα−/− and control mice were ovariectomized (OVX) and treated with vehicle or estradiol (0.5 μg/d) for 6 weeks. As expected, estradiol treatment increased the cortical bone thickness in femur, the cortical bone mechanical strength in tibia and the trabecular bone volume fraction in both femur and vertebrae in OVX control mice. Importantly, the estrogenic responses were substantially increased in OVX POMC-ERα−/− mice compared with the estrogenic responses in OVX control mice for cortical bone thickness (+126 ± 34%, P < .01) and mechanical strength (+193 ± 38%, P < .01). To test whether ERα in VMN is involved in the regulation of bone mass, ERα was silenced using an adeno-associated viral vector. Silencing of ERα in hypothalamic VMN resulted in unchanged bone mass. In conclusion, mice lacking ERα in POMC neurons display enhanced estrogenic response on cortical bone mass and mechanical strength. We propose that the balance between inhibitory effects of central ERα activity in hypothalamic POMC neurons in ARC and stimulatory peripheral ERα-mediated effects in bone determines cortical bone mass in female mice.

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NaQuinate selectively synergises with in vivo mechanical loading stimuli to enhance cortical bone mass and architectural modifications

Bone Reports ◽

10.1016/j.bonr.2021.100885 ◽

2021 ◽

Vol 14 ◽

pp. 100885

Author(s):

Behzad Javaheri ◽

Amy Lock ◽

Mark Hopkinson ◽

Samuel Monzem ◽

Yu-Mei Chang ◽

...

Keyword(s):

Bone Mass ◽

Cortical Bone ◽

Mechanical Loading ◽

Cortical Bone Mass

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Connexin Hemichannels with Prostaglandin Release in Anabolic Function of Bone to Mechanical Loading

10.1101/2021.10.15.464551 ◽

2021 ◽

Author(s):

Jean Jiang

Keyword(s):

Bone Formation ◽

Gap Junction ◽

Mechanical Loading ◽

Critical Role ◽

Dominant Negative ◽

Osteoblast Activity ◽

Prostaglandin Release ◽

Osteogenic Response ◽

Cortical Bone Mass

Mechanical stimulation, such as physical exercise, is essential for bone formation and health. Here, we demonstrate the critical role of osteocytic Cx43 hemichannels in anabolic function of bone in response to mechanical loading. Two transgenic mouse models, R76W and Δ130-136, expressing dominant-negative Cx43 mutants in osteocytes were adopted. Mechanical loading of tibial bone increased cortical bone mass and mechanical properties in wild-type and gap junction-impaired R76W mice through increased PGE2, endosteal osteoblast activity, and decreased sclerostin. These anabolic responses were impeded in gap junction/hemichannel-impaired Δ130-136 mice and accompanied by increased endosteal osteoclast activity. Specific inhibition of Cx43 hemichannels by Cx43(M1) antibody suppressed PGE2 secretion and impeded loading-induced endosteal osteoblast activity, bone formation and anabolic gene expression. PGE2 administration rescued the osteogenic response to mechanical loading impeded by impaired hemichannels. Together, osteocytic Cx43 hemichannels could be a potential new therapeutic target for treating bone loss and osteoporosis.

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Liver-derived IGF-I is not required for protection against osteoarthritis in male mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00330.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. E1150-E1157 ◽

Cited By ~ 1

Author(s):

Anna E. Törnqvist ◽

Antonia Sophocleous ◽

Stuart H. Ralston ◽

Claes Ohlsson ◽

Johan Svensson

Keyword(s):

Articular Cartilage ◽

Cortical Bone ◽

Cartilage Damage ◽

Lateral Side ◽

Male Mice ◽

Medial Side ◽

Calcified Cartilage ◽

Age Related ◽

Igf I ◽

And Control

Insulin-like growth factor-I (IGF-I) is anabolic for cartilage and important for cartilage integrity, which might suggest a connection between IGF-I and osteoarthritis (OA) development. However, the results of studies performed so far are conflicting, and we aimed to clarify the role of endocrine IGF-I in rodent OA. Male mice with inducible inactivation of circulating, liver-derived IGF-I (LI-IGF-I−/− mice, serum IGF-I reduced by ~80%) were used. Experimental OA was induced in young adult LI-IGF-I−/− and control mice by destabilization of the medial meniscus (DMM); age-related OA was also evaluated in 1-yr-old mice. DMM-operated LI-IGF-I−/− mice had thinner lateral subchondral bone plate in tibia compared with control mice, whereas osteophyte volume and articular cartilage damage were unaffected at the medial side of the DMM knee. However, the control mice but not the LI-IGF-I−/− mice also developed mild OA on the lateral side of the DMM knee compared with the unoperated knee. One-year-old LI-IGF-I−/− mice had lower mid-diaphyseal cortical bone area than the 1-yr-old control mice, whereas analyses of joint tissues displayed smaller osteophyte volume and thicker calcified cartilage than the control mice. There was no difference in OA severity in the articular cartilage between old LI-IGF-I−/− and control mice. Our study is the first to investigate whether there is an association between circulating IGF-I and OA in mice. We conclude that, although there is an ~80% reduction of circulating IGF-I and a decrease in cortical bone in male LI-IGF-I−/− mice, cartilage damage is clearly not intensified and may instead be slightly reduced.

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Combined Treatment With GH and IGF-I: Additive Effect on Cortical Bone Mass But Not on Linear Bone Growth in Female Rats

Endocrinology ◽

10.1210/en.2014-1160 ◽

2014 ◽

Vol 155 (12) ◽

pp. 4798-4807 ◽

Cited By ~ 10

Author(s):

Katja Sundström ◽

Therese Cedervall ◽

Claes Ohlsson ◽

Cecilia Camacho-Hübner ◽

Lars Sävendahl

Keyword(s):

Bone Mass ◽

Cortical Bone ◽

Growth Plate ◽

Bone Growth ◽

Combined Therapy ◽

Combined Treatment ◽

Female Rats ◽

Longitudinal Bone Growth ◽

Igf I ◽

Cortical Bone Mass

The growth-promoting effect of combined therapy with GH and IGF-I in normal rats is not known. We therefore investigated the efficacy of treatment with recombinant human (rh)GH and/or rhIGF-I on longitudinal bone growth and bone mass in intact, prepubertal, female Sprague-Dawley rats. rhGH was injected twice daily sc (5 mg/kg·d) and rhIGF-I continuously infused sc (2.2 or 4.4 mg/kg·d) for 28 days. Longitudinal bone growth was monitored by weekly x-rays of tibiae and nose-anus length measurements, and tibial growth plate histomorphology was analyzed. Bone mass was evaluated by peripheral quantitative computed tomography. In addition, serum levels of IGF-I, rat GH, acid labile subunit, IGF binding protein-3, 150-kDa ternary complex formation, and markers of bone formation and degradation were measured. Monotherapy with rhGH was more effective than rhIGF-I (4.4 mg/kg·d) to increase tibia and nose-anus length, whereas combined therapy did not further increase tibia, or nose-anus, lengths or growth plate height. In contrast, combined rhGH and rhIGF-I (4.4 mg/kg·d) therapy had an additive stimulatory effect on cortical bone mass vs rhGH alone. Combined treatment with rhGH and rhIGF-I resulted in markedly higher serum IGF-I concentrations vs rhGH alone but did not compromise the endogenous secretion of GH. We conclude that rhIGF-I treatment augments cortical bone mass but does not further improve bone growth in rhGH-treated young, intact, female rats.

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