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Article ; Online: The cytoskeleton and connected elements in bone cell mechano-transduction.

Gould, Nicole R / Torre, Olivia M / Leser, Jenna M / Stains, Joseph P

2021 Volume 149, Page(s) 115971

Abstract: Bone is a mechano-responsive tissue that adapts to changes in its mechanical environment. Increases in strain lead to increased bone mass acquisition, whereas decreases in strain lead to a loss of bone mass. Given that mechanical stress is a regulator of ...

Abstract	Bone is a mechano-responsive tissue that adapts to changes in its mechanical environment. Increases in strain lead to increased bone mass acquisition, whereas decreases in strain lead to a loss of bone mass. Given that mechanical stress is a regulator of bone mass and quality, it is important to understand how bone cells sense and transduce these mechanical cues into biological changes to identify druggable targets that can be exploited to restore bone cell mechano-sensitivity or to mimic mechanical load. Many studies have identified individual cytoskeletal components - microtubules, actin, and intermediate filaments - as mechano-sensors in bone. However, given the high interconnectedness and interaction between individual cytoskeletal components, and that they can assemble into multiple discreet cellular structures, it is likely that the cytoskeleton as a whole, rather than one specific component, is necessary for proper bone cell mechano-transduction. This review will examine the role of each cytoskeletal element in bone cell mechano-transduction and will present a unified view of how these elements interact and work together to create a mechano-sensor that is necessary to control bone formation following mechanical stress.
MeSH term(s)	Actin Cytoskeleton ; Actins ; Cytoskeleton ; Intermediate Filaments ; Microtubules ; Osteocytes
Chemical Substances	Actins
Language	English
Publishing date	2021-04-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	632515-4
ISSN	1873-2763 ; 8756-3282
ISSN (online)	1873-2763
ISSN	8756-3282
DOI	10.1016/j.bone.2021.115971
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Zs.MO 332: Show issues

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Article ; Online: Connexin43 and the Intercellular Signaling Network Regulating Skeletal Remodeling.

Moorer, Megan C / Stains, Joseph P

Current osteoporosis reports

2017 Volume 15, Issue 1, Page(s) 24–31

Abstract: Purpose of the review: This review highlights recent developments into how intercellular communication through connexin43 facilitates bone modeling and remodeling.: Recent findings: Connexin43 is required for both skeletal development and maintenance, ...

Abstract	Purpose of the review: This review highlights recent developments into how intercellular communication through connexin43 facilitates bone modeling and remodeling. Recent findings: Connexin43 is required for both skeletal development and maintenance, particularly in cortical bone, where it carries out multiple functions, including preventing osteoclastogenesis, restraining osteoprogenitor proliferation, promoting osteoblast differentiation, coordinating organized collagen matrix deposition, and maintaining osteocyte survival. Emerging data shows that connexin43 regulates both the exchange of small molecules among osteoblast lineage cells and the docking of signaling proteins to the gap junction, affecting the efficiency of signal transduction. Understanding how and what connexin43 communicates to coordinate tissue remodeling has therapeutic implications in bone. Altering the information shared by intercellular communication and/or targeting the recruitment of signaling machinery to the gap junction could be used to impact the skeletal homeostatic set point, either driving osteogenesis or inhibiting resorption.
Language	English
Publishing date	2017-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2186581-4
ISSN	1544-2241 ; 1544-1873
ISSN (online)	1544-2241
ISSN	1544-1873
DOI	10.1007/s11914-017-0345-4
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Article ; Online: Osteoblast-lineage calcium/calmodulin-dependent kinase 2 delta and gamma regulates bone mass and quality.

Leser, Jenna M / Torre, Olivia M / Gould, Nicole R / Guo, Qiaoyue / Buck, Heather V / Kodama, Joe / Otsuru, Satoru / Stains, Joseph P

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 47, Page(s) e2304492120

Abstract: Bone regulates its mass and quality in response to diverse mechanical, hormonal, and local signals. The bone anabolic or catabolic responses to these signals are often received by osteocytes, which then coordinate the activity of osteoblasts and ... ...

Abstract	Bone regulates its mass and quality in response to diverse mechanical, hormonal, and local signals. The bone anabolic or catabolic responses to these signals are often received by osteocytes, which then coordinate the activity of osteoblasts and osteoclasts on bone surfaces. We previously established that calcium/calmodulin-dependent kinase 2 (CaMKII) is required for osteocytes to respond to some bone anabolic cues in vitro. However, a role for CaMKII in bone physiology in vivo is largely undescribed. Here, we show that conditional codeletion of the most abundant isoforms of CaMKII (delta and gamma) in mature osteoblasts and osteocytes [Ocn-cre:
MeSH term(s)	Mice ; Animals ; Calcium/metabolism ; Calmodulin/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Osteoblasts/metabolism ; Osteocytes/metabolism ; Phosphates/metabolism ; Hypophosphatemia
Chemical Substances	Calcium (SY7Q814VUP) ; Calmodulin ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 (EC 2.7.11.17) ; Phosphates ; Camk2g protein, mouse (EC 2.7.11.17)
Language	English
Publishing date	2023-11-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2304492120
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Article ; Online: DeepFreeze 3D-biofabrication for Bioengineering and Storage of Stem Cells in Thick and Large-Scale Human Tissue Analogs.

Kumar, Alok / Brown, Robert A / Roufaeil, Daniel Benyamien / Gupta, Aditi / Lipford, Erika L / Muthusamy, Divya / Zalzman, Amihai / Hertzano, Ronna / Lowe, Tao / Stains, Joseph P / Zalzman, Michal

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

2024 Volume 11, Issue 11, Page(s) e2306683

Abstract: 3D bioprinting holds great promise for meeting the increasing need for transplantable tissues and organs. However, slow printing, interlayer mixing, and the extended exposure of cells to non-physiological conditions in thick structures still hinder ... ...

Abstract	3D bioprinting holds great promise for meeting the increasing need for transplantable tissues and organs. However, slow printing, interlayer mixing, and the extended exposure of cells to non-physiological conditions in thick structures still hinder clinical applications. Here the DeepFreeze-3D (DF-3D) procedure and bioink for creating multilayered human-scale tissue mimetics is presented for the first time. The bioink is tailored to support stem cell viability, throughout the rapid freeform DF-3D biofabrication process. While the printer nozzle is warmed to room temperature, each layer solidifies at contact with the stage (-80 °C), or the subsequent layers, ensuring precise separation. After thawing, the encapsulated stem cells remain viable without interlayer mixing or delamination. The composed cell-laden constructs can be cryogenically stored and thawed when needed. Moreover, it is shown that under inductive conditions the stem cells differentiate into bone-like cells and grow for months after thawing, to form large tissue-mimetics in the scale of centimeters. This is important, as this approach allows the generation and storage of tissue mimetics in the size and thickness of human tissues. Therefore, DF-3D biofabrication opens new avenues for generating off-the-shelf human tissue analogs. It further holds the potential for regenerative treatments and for studying tissue pathologies caused by disease, tumor, or trauma.
MeSH term(s)	Humans ; Tissue Engineering/methods ; Tissue Scaffolds/chemistry ; Printing, Three-Dimensional ; Bioprinting/methods ; Bioengineering ; Stem Cells
Language	English
Publishing date	2024-01-06
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2808093-2
ISSN	2198-3844 ; 2198-3844
ISSN (online)	2198-3844
ISSN	2198-3844
DOI	10.1002/advs.202306683
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Article ; Online: A Functional Assay to Assess Connexin 43-Mediated Cell-to-Cell Communication of Second Messengers in Cultured Bone Cells.

Stains, Joseph P / Civitelli, Roberto

Methods in molecular biology (Clifton, N.J.)

2016 Volume 1437, Page(s) 193–201

Abstract: Cell-to-cell transfer of small molecules is a fundamental way by which multicellular organisms coordinate function. Recent work has highlighted the complexity of biologic responses downstream of gap junctions. As the connexin-regulated effectors are ... ...

Abstract	Cell-to-cell transfer of small molecules is a fundamental way by which multicellular organisms coordinate function. Recent work has highlighted the complexity of biologic responses downstream of gap junctions. As the connexin-regulated effectors are coming into focus, there is a need to develop functional assays that allow specific testing of biologically relevant second messengers. Here, we describe a modification of the classic gap junction parachute assay to assess biologically relevant molecules passed through gap junctions.
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-3664-9_14
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Article: Methylsulfonylmethane Increases the Alveolar Bone Density of Mandibles in Aging Female Mice.

Aljohani, Hanan / Senbanjo, Linda T / Al Qranei, Mohammed / Stains, Joseph P / Chellaiah, Meenakshi A

Frontiers in physiology

2021 Volume 12, Page(s) 708905

Abstract: Methylsulfonylmethane (MSM) is a naturally occurring anti-inflammatory compound that effectively treats multiple degenerative diseases such as osteoarthritis and acute pancreatitis. Our previous studies have demonstrated the ability of MSM to ... ...

Abstract	Methylsulfonylmethane (MSM) is a naturally occurring anti-inflammatory compound that effectively treats multiple degenerative diseases such as osteoarthritis and acute pancreatitis. Our previous studies have demonstrated the ability of MSM to differentiate stem cells from human exfoliated deciduous (SHED) teeth into osteoblast-like cells. This study examined the systemic effect of MSM in 36-week-old aging C57BL/6 female mice
Language	English
Publishing date	2021-10-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2021.708905
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Article ; Online: Aging, Osteo-Sarcopenia, and Musculoskeletal Mechano-Transduction.

Leser, Jenna M / Harriot, Anicca / Buck, Heather V / Ward, Christopher W / Stains, Joseph P

Frontiers in rehabilitation sciences

2021 Volume 2

Abstract: The decline in the mass and function of bone and muscle is an inevitable consequence of healthy aging with early onset and accelerated decline in those with chronic disease. Termed osteo-sarcopenia, this condition predisposes the decreased activity, ... ...

Abstract	The decline in the mass and function of bone and muscle is an inevitable consequence of healthy aging with early onset and accelerated decline in those with chronic disease. Termed osteo-sarcopenia, this condition predisposes the decreased activity, falls, low-energy fractures, and increased risk of co-morbid disease that leads to musculoskeletal frailty. The biology of osteo-sarcopenia is most understood in the context of systemic neuro-endocrine and immune/inflammatory alterations that drive inflammation, oxidative stress, reduced autophagy, and cellular senescence in the bone and muscle. Here we integrate these concepts to our growing understanding of how bone and muscle senses, responds and adapts to mechanical load. We propose that age-related alterations in cytoskeletal mechanics alter load-sensing and mechano-transduction in bone osteocytes and muscle fibers which underscores osteo-sarcopenia. Lastly, we examine the evidence for exercise as an effective countermeasure to osteo-sarcopenia.
Language	English
Publishing date	2021-12-06
Publishing country	Switzerland
Document type	Journal Article
ISSN	2673-6861
ISSN (online)	2673-6861
DOI	10.3389/fresc.2021.782848
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Article: Peptidomimetic inhibitor of L-plastin reduces osteoclastic bone resorption in aging female mice.

Aljohani, Hanan / Stains, Joseph P / Majumdar, Sunipa / Srinivasan, Deepa / Senbanjo, Linda / Chellaiah, Meenakshi A

Bone research

2021 Volume 9, Issue 1, Page(s) 22

Abstract: L-plastin (LPL) was identified as a potential regulator of the actin-bundling process involved in forming nascent sealing zones (NSZs), which are precursor zones for mature sealing zones. TAT-fused cell-penetrating small molecular weight LPL peptide (TAT- ...

Abstract	L-plastin (LPL) was identified as a potential regulator of the actin-bundling process involved in forming nascent sealing zones (NSZs), which are precursor zones for mature sealing zones. TAT-fused cell-penetrating small molecular weight LPL peptide (TAT- MARGSVSDEE, denoted as an inhibitory LPL peptide) attenuated the formation of NSZs and impaired bone resorption in vitro in osteoclasts. Also, the genetic deletion of LPL in mice demonstrated decreased eroded perimeters and increased trabecular bone density. In the present study, we hypothesized that targeting LPL with the inhibitory LPL peptide in vivo could reduce osteoclast function and increase bone density in a mice model of low bone mass. We injected aging C57BL/6 female mice (36 weeks old) subcutaneously with the inhibitory and scrambled peptides of LPL for 14 weeks. Micro-CT and histomorphometry analyses demonstrated an increase in trabecular bone density of femoral and tibial bones with no change in cortical thickness in mice injected with the inhibitory LPL peptide. A reduction in the serum levels of CTX-1 peptide suggests that the increase in bone density is associated with a decrease in osteoclast function. No changes in bone formation rate and mineral apposition rate, and the serum levels of P1NP indicate that the inhibitory LPL peptide does not affect osteoblast function. Our study shows that the inhibitory LPL peptide can block osteoclast function without impairing the function of osteoblasts. LPL peptide could be developed as a prospective therapeutic agent to treat osteoporosis.
Language	English
Publishing date	2021-04-09
Publishing country	China
Document type	Journal Article
ZDB-ID	2803313-9
ISSN	2095-6231 ; 2095-4700
ISSN (online)	2095-6231
ISSN	2095-4700
DOI	10.1038/s41413-020-00135-9
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Article ; Online: Connexins and pannexins in the skeleton: gap junctions, hemichannels and more.

Plotkin, Lilian I / Stains, Joseph P

Cellular and molecular life sciences : CMLS

2015 Volume 72, Issue 15, Page(s) 2853–2867

Abstract: Regulation of bone homeostasis depends on the concerted actions of bone-forming osteoblasts and bone-resorbing osteoclasts, controlled by osteocytes, cells derived from osteoblasts surrounded by bone matrix. The control of differentiation, viability and ... ...

Abstract	Regulation of bone homeostasis depends on the concerted actions of bone-forming osteoblasts and bone-resorbing osteoclasts, controlled by osteocytes, cells derived from osteoblasts surrounded by bone matrix. The control of differentiation, viability and function of bone cells relies on the presence of connexins. Connexin43 regulates the expression of genes required for osteoblast and osteoclast differentiation directly or by changing the levels of osteocytic genes, and connexin45 may oppose connexin43 actions in osteoblastic cells. Connexin37 is required for osteoclast differentiation and its deletion results in increased bone mass. Less is known on the role of connexins in cartilage, ligaments and tendons. Connexin43, connexin45, connexin32, connexin46 and connexin29 are expressed in chondrocytes, while connexin43 and connexin32 are expressed in ligaments and tendons. Similarly, although the expression of pannexin1, pannexin2 and pannexin3 has been demonstrated in bone and cartilage cells, their function in these tissues is not fully understood.
MeSH term(s)	Animals ; Bone and Bones/metabolism ; Bone and Bones/physiology ; Connexins/metabolism ; Gap Junctions/metabolism ; Gap Junctions/physiology ; Homeostasis/physiology ; Humans ; Ion Channels/metabolism
Chemical Substances	Connexins ; Ion Channels
Language	English
Publishing date	2015-08
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-015-1963-6
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Zs.A 195: Show issues

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Article ; Online: Connexins in the skeleton.

Stains, Joseph P / Civitelli, Roberto

Seminars in cell & developmental biology

2015 Volume 50, Page(s) 31–39

Abstract: Shaping of the skeleton (modeling) and its maintenance throughout life (remodeling) require coordinated activity among bone forming (osteoblasts) and resorbing cells (osteoclasts) and osteocytes (bone embedded cells). The gap junction protein connexin43 ( ...

Abstract	Shaping of the skeleton (modeling) and its maintenance throughout life (remodeling) require coordinated activity among bone forming (osteoblasts) and resorbing cells (osteoclasts) and osteocytes (bone embedded cells). The gap junction protein connexin43 (Cx43) has emerged as a key modulator of skeletal growth and homeostasis. The skeletal developmental abnormalities present in oculodentodigital and craniometaphyseal dysplasias, both linked to Cx43 gene (GJA1) mutations, demonstrate that the skeleton is a major site of Cx43 action. Via direct action on osteolineage cells, including altering production of pro-osteoclastogenic factors, Cx43 contributes to peak bone mass acquisition, cortical modeling of long bones, and maintenance of bone quality. Cx43 also contributes in diverse ways to bone responsiveness to hormonal and mechanical signals. Skeletal biology research has revealed the complexity of Cx43 function; in addition to forming gap junctions and "hemichannels", Cx43 provides a scaffold for signaling molecules. Hence, Cx43 actively participates in generation and modulation of cellular signals driving skeletal development and homeostasis. Pharmacological interference with Cx43 may in the future help remedy deterioration of bone quality occurring with aging, disuse and hormonal imbalances.
MeSH term(s)	Animals ; Bone Development ; Bone Diseases/metabolism ; Bone and Bones/metabolism ; Connexins/chemistry ; Connexins/metabolism ; Homeostasis ; Humans ; Translational Research, Biomedical
Chemical Substances	Connexins
Language	English
Publishing date	2015-12-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1312473-0
ISSN	1096-3634 ; 1084-9521
ISSN (online)	1096-3634
ISSN	1084-9521
DOI	10.1016/j.semcdb.2015.12.017
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