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Bone biologies

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Parathyroid hormone receptor (PTH1R) signaling mediates breast cancer metastasis to bone in mice
Srilatha Swami, … , Vaisakh Nair, Joy Y. Wu
Srilatha Swami, … , Vaisakh Nair, Joy Y. Wu
Published January 24, 2023
Citation Information: JCI Insight. 2023. https://doi.org/10.1172/jci.insight.157390.
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Parathyroid hormone receptor (PTH1R) signaling mediates breast cancer metastasis to bone in mice

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Abstract

Bone metastases are a common complication of breast cancer. We have demonstrated that intermittent administration of parathyroid hormone (PTH [1-34]) reduces the incidence of bone metastases in murine models of breast cancer by acting on osteoblasts to alter the bone microenvironment. Here, we examined the role of PTH receptor (PTH1R)-mediated signaling in both osteoblasts and breast cancer cells in influencing bone metastases. In mice with impaired PTH1R signaling in osteoblasts, intermittent PTH did not reduce bone metastasis. Intermittent PTH also failed to reduce bone metastasis when expression of PTH1R was knocked down in 4T1 murine breast cancer cells by shRNA. In 4T1 breast cancer cells, PTH decreased expression of PTH-related protein (PTHrP), implicated in the vicious cycle of bone metastases. Knockdown of PTHrP in 4T1 cells significantly reduced migration towards MC3T3-E1 osteoblasts, and migration was further inhibited by treatment with intermittent PTH. Conversely, overexpression of PTHrP in 4T1 cells increased migration towards MC3T3-E1 osteoblasts and this was not inhibited by PTH. In conclusion, PTH1R expression is crucial in both osteoblasts and breast cancer cells for PTH to reduce bone metastases and in breast cancer cells this may be mediated in part by suppression of PTHrP.

Authors

Srilatha Swami, Hui Zhu, Aria Nisco, Takaharu Kimura, Matthew J. Kim, Vaisakh Nair, Joy Y. Wu

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Minocycline-induced disruption of the intestinal FXR-FGF15 axis impairs osteogenesis in mice
Matthew D. Carson, … , Caroline Westwater, Chad M. Novince
Matthew D. Carson, … , Caroline Westwater, Chad M. Novince
Published November 22, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.160578.
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Minocycline-induced disruption of the intestinal FXR-FGF15 axis impairs osteogenesis in mice

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Abstract

Antibiotic-induced shifts in the indigenous gut microbiota influence normal skeletal maturation. Current theory implies that gut microbiota actions on bone occur through a direct gut-bone signaling axis. However, our prior work supports that a gut-liver signaling axis contributes to gut microbiota effects on bone. Purpose was to investigate the effects of minocycline, a systemic antibiotic treatment for adolescent acne, on pubertal/post-pubertal skeletal maturation. Sex-matched specific-pathogen-free(SPF) and germ-free(GF) C57BL/6T mice were administered a clinically relevant minocycline dose from age 6-12 weeks. Minocycline caused dysbiotic shifts in the gut bacteriome and impaired skeletal maturation in SPF mice, but did not alter the skeletal phenotype in GF mice. Minocycline administration in SPF mice disrupted the intestinal farnesoid X receptor(FXR)-fibroblast growth factor 15(FGF15) axis, a gut-liver endocrine axis supporting systemic bile acid homeostasis. Minocycline-treated SPF mice had increased serum conjugated bile acids that are FXR antagonists, suppressed osteoblast function, decreased bone mass, impaired bone microarchitecture and fracture resistance. Stimulating osteoblasts with the serum bile acid profile from minocycline-treated SPF mice recapitulated the suppressed osteogenic phenotype found in vivo, which was mediated through attenuated FXR-signaling. This work introduces bile acids as a novel mediator of gut-liver signaling actions contributing to gut microbiota effects on bone.

Authors

Matthew D. Carson, Amy J. Warner, Jessica D. Hathaway-Schrader, Vincenza L. Geiser, Joseph D. Kim, Joy E. Gerasco, William D. Hill, John J. Lemasters, Alexander V. Alekseyenko, Yongren Wu, Hai Yao, Jose I. Aguirre, Caroline Westwater, Chad M. Novince

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CCL3 in bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice
Degang Yu, … , Guangwang Liu, Zanjing Zhai
Degang Yu, … , Guangwang Liu, Zanjing Zhai
Published November 15, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.159107.
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CCL3 in bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice

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The central physiological role of the bone marrow renders the bone marrow stromal cells (BMSCs) particularly sensitive to aging. With bone aging, BMSCs acquire a differentiation potential bias in favor of adipogenesis over osteogenesis, and the underlying molecular mechanisms remain unclear. Herein, we investigated the factors underlying age-related changes in the bone marrow, and their roles in BMSCs differentiation. Antibody array revealed that C-C motif chemokine ligand 3 (CCL3) accumulation occurred in the serum of naturally aged mice along with bone aging phenotypes, including bone loss, bone marrow adiposity, and imbalanced BMSCs differentiation. In vivo Ccl3 deletion could rescue these phenotypes in aged mice. CCL3 improved the adipogenic differentiation potential of BMSCs, with a positive feedback loop between CCL3 and C/EBPα. CCL3 activated C/EBPα expression via STAT3, while C/EBPα activated CCL3 expression through direct promoter binding, facilitated by DNA hypo-methylation. Moreover, CCL3 inhibited BMSCs osteogenic differentiation potential by blocking β-catenin activity mediated by ERK-activated DKK-1 upregulation. Blocking CCL3 in vivo via neutralization antibodies ameliorated trabecular bone loss and bone marrow adiposity in aged mice. This study provides insights regarding age-related bone loss and bone marrow adiposity pathogenesis, and lays a foundation for the identification of new targets for senile osteoporosis treatment.

Authors

Degang Yu, Shuhong Zhang, Chao Ma, Sen Huang, Long Xu, Jun Liang, Huiwu Li, Qiming Fan, Guangwang Liu, Zanjing Zhai

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Longitudinal associations of insulin resistance with change in bone mineral density in midlife women
Albert Shieh, … , Preethi Srikanthan, Arun S. Karlamangla
Albert Shieh, … , Preethi Srikanthan, Arun S. Karlamangla
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e162085. https://doi.org/10.1172/jci.insight.162085.
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Longitudinal associations of insulin resistance with change in bone mineral density in midlife women

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Abstract

BACKGROUND The effects of insulin resistance on bone mineral density (BMD) are unclear.METHODS In Study of Women’s Health Across the Nation (SWAN) participants, we used multivariable regression to test average insulin resistance (homeostatic model assessment of insulin resistance, HOMA-IR) and rate of change in insulin resistance as predictors of rate of change in lumbar spine (LS) and femoral neck (FN) BMD in 3 stages: premenopause (n = 861), menopause transition (MT) (n = 571), and postmenopause (n = 693). Models controlled for age, average BW, change in BW, cigarette use, race and ethnicity, and study site.RESULTS The relation between HOMA-IR and BMD decline was biphasic. When average log2HOMA-IR was less than 1.5, greater HOMA-IR was associated with slower BMD decline; i.e., each doubling of average HOMA-IR in premenopause was associated with a 0.0032 (P = 0.01, LS) and 0.0041 (P = 0.004, FN) g/cm2 per year slower BMD loss. When greater than or equal to 1.5, average log2HOMA-IR was not associated with BMD change. In women in whom HOMA-IR decreased in premenopause, the association between the HOMA-IR change rate and BMD change rate was positive; i.e, slower HOMA-IR decline was associated with slower BMD loss. In women in whom insulin resistance increased in premenopause, the association was negative; i.e, faster HOMA-IR rise was associated with faster BMD decline. Associations of average HOMA-IR and HOMA-IR change rate with BMD change rate were similar in postmenopause, but weaker during the MT.CONCLUSION When it decreases, insulin resistance is associated with BMD preservation; when it increases, insulin resistance is associated with BMD loss.FUNDING The SWAN has grant support from the NIH of the Department of Health and Human Services (DHHS) through the NIH National Institute on Aging (NIA), National Institute of Nursing Research (NINR), and Office of Research on Women’s Health (ORWH) (grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495, and U19AG063720).

Authors

Albert Shieh, Gail A. Greendale, Jane A. Cauley, Preethi Srikanthan, Arun S. Karlamangla

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Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp mice
Achim Buck, … , Reinhold G. Erben, Axel Walch
Achim Buck, … , Reinhold G. Erben, Axel Walch
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e162138. https://doi.org/10.1172/jci.insight.162138.
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Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp mice

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Abstract

Patients with the renal phosphate–wasting disease X-linked hypophosphatemia (XLH) and Hyp mice, the murine homolog of XLH, are characterized by loss-of-function mutations in phosphate-regulating endopeptidase homolog X-linked (PHEX), leading to excessive secretion of the bone-derived phosphotropic hormone FGF23. The mineralization defect in patients with XLH and Hyp mice is caused by a combination of hypophosphatemia and local accumulation of mineralization-inhibiting molecules in bone. However, the mechanism by which PHEX deficiency regulates bone cell metabolism remains elusive. Here, we used spatial metabolomics by employing matrix-assisted laser desorption/ionization (MALDI) Fourier-transform ion cyclotron resonance mass spectrometry imaging (MSI) of undecalcified bone cryosections to characterize in situ metabolic changes in bones of Hyp mice in a holistic, unbiased manner. We found complex changes in Hyp bone metabolism, including perturbations in pentose phosphate, purine, pyrimidine, and phospholipid metabolism. Importantly, our study identified an upregulation of several biochemical pathways involved in intra- and extracellular production of the mineralization inhibitor pyrophosphate in the bone matrix of Hyp mice. Our data emphasize the utility of MSI–based spatial metabolomics in bone research and provide holistic in situ insights as to how Phex deficiency–induced changes in biochemical pathways in bone cells are linked to impaired bone mineralization.

Authors

Achim Buck, Verena M. Prade, Thomas Kunzke, Reinhold G. Erben, Axel Walch

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Increased joint loading induces subchondral bone loss of temporomandibular joint via the RANTES-CCRs-Akt2 axis
Shi-Yang Feng, … , Yi-Xiang Wang, Kai-Yuan Fu
Shi-Yang Feng, … , Yi-Xiang Wang, Kai-Yuan Fu
Published September 29, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.158874.
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Increased joint loading induces subchondral bone loss of temporomandibular joint via the RANTES-CCRs-Akt2 axis

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Abstract

Early-stage temporomandibular joint osteoarthritis (TMJOA) is characterized by excessive subchondral bone loss. Emerging evidence suggests that TMJ disc displacement is involved, but the pathogenic mechanism remains unclear. Here, we established a rat model of TMJOA that simulated disc displacement and a capacitance-based force sensing system to directly measure articular surface pressure in vivo. Micro-CT, histological staining, immunofluorescence staining, immunohistochemistry staining, and Western blot were used to assess pathological changes and underlying mechanism of TMJOA in the rat model in vivo as well as in RAW264.7 cells in vitro. We found that disc displacement led to significantly higher pressure on articular surface, which caused subchondral bone loss rapidly via activation of RANTES-CCRs-Akt2 axis. Inhibition of RANTES or Akt2 attenuated subchondral bone loss and resulted in improved subchondral bone microstructure. Cytological studies substantiated that RANTES regulated osteoclast formation by binding to its receptor CCRs and activating Akt2 pathway. The clinical evidence further supported that RANTES was a potential biomarker for predicting subchondral bone loss in early-stage TMJOA. Taken together, this study demonstrates important functions of RANTES-CCRs-Akt2 axis in the regulation of subchondral bone remodeling and provides further knowledge of how disc displacement causes TMJOA.

Authors

Shi-Yang Feng, Jie Lei, Yu-Xiang Li, Wen-Ge Shi, Ran-Ran Wang, Adrian Ujin Yap, Yi-Xiang Wang, Kai-Yuan Fu

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Macrophage TGFβ signaling is critical for wound healing with heterotopic ossification after trauma
Nicole K. Patel, … , Amanda K. Huber, Benjamin Levi
Nicole K. Patel, … , Amanda K. Huber, Benjamin Levi
Published September 13, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.144925.
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Macrophage TGFβ signaling is critical for wound healing with heterotopic ossification after trauma

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Abstract

Transforming growth factor beta 1 (TGFβ1) plays a central role in normal and aberrant wound healing, but the precise mechanism in the local environment remains elusive. Here, using a mouse model of aberrant wound healing resulting in heterotopic ossification (HO) after traumatic injury, we find autocrine TGFβ1 signaling in macrophages, and not mesenchymal stem/progenitor cells (MPCs), is critical in HO formation. In-depth single cell transcriptomic and epigenomic analyses in combination with immunostaining of cells from the injury site demonstrate increased TGFβ1 signaling in early infiltrating macrophages, with open chromatin regions in TGFβ1 stimulated genes at binding sites specific for transcription factors of activated TGFβ1 (SMAD2/3). Genetic deletion of TGFβ1 receptor type 1, (Tgfbr1;Alk5) in macrophages, results in increased HO, with a trend toward decreased tendinous HO. To bypass the effect seen by altering the receptor we administered a systemic treatment with TGFβ1/3 ligand trap TGFβRII-Fc, which results in decreased HO formation and a delay macrophage infiltration to the injury site. Overall, our data support the role of the TGFβ1/ALK5 signaling pathway in HO.

Authors

Nicole K. Patel, Johanna H. Nunez, Michael Sorkin, Simone Marini, Chase A. Pagani, Amy L. Strong, Charles D. Hwang, Shuli Li, Karthik R. Padmanabhan, Ravi Kumar, Alec C. Bancroft, Joseph A. Greenstein, Reagan Nelson, Husain A. Rasheed, Nicholas Livingston, Kaetlin Vasquez, Amanda K. Huber, Benjamin Levi

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Constitutive bone marrow adipocytes suppress local bone formation
Ziru Li, … , Clifford J. Rosen, Ormond A. MacDougald
Ziru Li, … , Clifford J. Rosen, Ormond A. MacDougald
Published September 1, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.160915.
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Constitutive bone marrow adipocytes suppress local bone formation

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Abstract

Bone marrow adipocytes (BMAd) are a unique cell population derived from bone marrow mesenchymal progenitors and marrow adipogenic lineage precursors. Although they have long been considered to be a space-filler within bone cavities, recent studies have revealed important physiological roles in hematopoiesis and bone metabolism. To date, the approaches used to study BMAd function have been confounded by contributions by non-marrow adipocytes or by bone marrow stromal cells. To address this gap in the field, we have developed a BMAd-specific Cre mouse model to deplete BMAds by expression of diphtheria toxin A (DTA), or by deletion of peroxisome proliferator-activated receptor gamma (Pparg). We found that DTA-induced loss of BMAds results in decreased hematopoietic stem and progenitor cell numbers and increased bone mass in BMAd-enriched locations, including the distal tibiae and caudal vertebrae. Elevated bone mass appears to be secondary to enhanced endosteal bone formation, suggesting a local effect caused by depletion of BMAd. Augmented bone formation with BMAd-depletion protects mice from bone loss induced by caloric restriction or ovariectomy, and facilitates the bone healing process after fracture. Finally, ablation of Pparg also reduces BMAd numbers and largely recapitulates high bone mass phenotypes observed with DTA-induced BMAd depletion.

Authors

Ziru Li, Devika P. Bagchi, Junxiong Zhu, Emily Bowers, Hui Yu, Julie Hardij, Hiroyuki Mori, Katrina Granger, Jonathan D. Skjaerlund, Gurjit S. Mandair, Simin Abrishami, Kanakadurga Singer, Kurt D. Hankenson, Clifford J. Rosen, Ormond A. MacDougald

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Multi-parametric MRI to quantify disease and treatment response in mice with myeloproliferative neoplasms
Tanner H. Robison, … , Brian D. Ross, Gary D. Luker
Tanner H. Robison, … , Brian D. Ross, Gary D. Luker
Published August 23, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.161457.
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Multi-parametric MRI to quantify disease and treatment response in mice with myeloproliferative neoplasms

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Abstract

Histopathology, the standard method to assess bone marrow in hematologic malignancies such as myeloproliferative neoplasms (MPNs), suffers from notable limitations in both research and clinical settings. Bone marrow biopsies in patients fail to detect disease heterogeneity; may yield a non-diagnostic sample; and cannot be repeated frequently in clinical oncology. Endpoint histopathology precludes monitoring disease progression and response to therapy in the same mouse over time, missing likely variations among mice. To overcome these shortcomings, we used magnetic resonance imaging (MRI) to measure changes in cellularity, macromolecular constituents, and fat versus hematopoietic cells in bone marrow using diffusion-weighted imaging, magnetization transfer, and chemical shift encoded fat imaging. Combining metrics from these imaging parameters revealed dynamic alterations in bone marrow following myeloablative radiation and transplantation. In a mouse MPLW515L bone marrow transplant model of MPN, MRI detected effects of a JAK2 inhibitor, ruxolitinib, within five days of initiating treatment and identified differing kinetics of treatment responses in sub-regions of the tibia. Histopathology validated MRI results for bone marrow composition and heterogeneity. Anatomic MRI scans also showed reductions in spleen volume during treatment. These findings establish an innovative, clinically translatable MRI approach to quantify spatial and temporal changes in bone marrow in MPN.

Authors

Tanner H. Robison, Manisha Solipuram, Kevin Heist, Ghoncheh Amouzandeh, Winston Y. Lee, Brock A. Humphries, Johanna M. Buschhaus, Avinash Bevoor, Anne Zhang, Kathryn E. Luker, Kristen Pettit, Moshe Talpaz, Dariya Malyarenko, Thomas L. Chenevert, Brian D. Ross, Gary D. Luker

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Macrophage miR-149-5p induction is a key driver and therapeutic target for BRONJ
Xin Shen, … , Rongyao Xu, Hongbing Jiang
Xin Shen, … , Rongyao Xu, Hongbing Jiang
Published August 22, 2022
Citation Information: JCI Insight. 2022;7(16):e159865. https://doi.org/10.1172/jci.insight.159865.
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Macrophage miR-149-5p induction is a key driver and therapeutic target for BRONJ

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Abstract

Bisphosphonate-related (BP-related) osteonecrosis of the jaw (BRONJ) is one of the severe side effects of administration of BPs, such as zoledronic acid (ZA), which can disrupt the patient’s quality of life. Although the direct target of skeletal vasculature and bone resorption activity by BPs has been phenomenally observed, the underlying mechanism in BRONJ remains largely elusive. Thus, it is urgently necessary to discover effective therapeutic targets based on the multifaceted underlying mechanisms in the development of BRONJ. Here, we determined the inhibitory role of ZA-treated macrophages on osteoclast differentiation and type H vessel formation during tooth extraction socket (TES) healing. Mechanistically, ZA activated the NF-κB signaling pathway and then induced p65 nuclear translocation in macrophages to promote miR-149-5p transcription, resulting in impaired osteoclast differentiation via directly binding to the Traf6 3′-UTR region. Moreover, we identified that miR-149-5p–loaded extracellular vesicles derived from ZA-treated bone marrow–derived macrophages could regulate biological functions of endothelial cells via the Rap1a/Rap1b/VEGFR2 pathway. Furthermore, local administration of chemically modified antagomiR-149-5p was proven to be therapeutically effective in BRONJ mice. In conclusion, our findings illuminate the dual effects of miR-149-5p on skeletal angiogenesis and bone remolding, suggesting it as a promising preventive and therapeutic target for BRONJ.

Authors

Xin Shen, Weiwen Zhu, Ping Zhang, Yu Fu, Jie Cheng, Laikui Liu, Rongyao Xu, Hongbing Jiang

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