TGFβ regulation of perilacunar/canalicular remodeling is sexually dimorphic

Dole, Neha S; Yee, Cristal S.; Mazur, Courtney M.; Acevedo, Claire; Alliston, Tamara

doi:10.1101/737395

Cited by 6 publications

(10 citation statements)

References 71 publications

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“…OA is more prevalent in women than in men, particularly after menopause, demonstrating a need to better understand the sex-specific pathogenesis of OA (44). We have recently shown that osteocytic TGFβ signaling induces PLR in a sex-specific manner (28). While male TβRII ocy−/− mice demonstrate hallmarks of suppressed PLR in the cortical bone, including blunted canalicular networks, reduced expression of PLR enzymes, and defective bone quality, PLR and bone quality remain intact in female TβRII ocy−/− mice (28).…”

Section: Discussionmentioning

confidence: 99%

“…We have recently shown that osteocytic TGFβ signaling induces PLR in a sex-specific manner (28). While male TβRII ocy−/− mice demonstrate hallmarks of suppressed PLR in the cortical bone, including blunted canalicular networks, reduced expression of PLR enzymes, and defective bone quality, PLR and bone quality remain intact in female TβRII ocy−/− mice (28). This set of observations remained true in this study, where 16-week-old male TβRII ocy−/− mice showed a disruption of the subchondral bone canalicular network, increased SBP | 423 thickness, and signs of worsened joint degeneration, while female TβRII ocy−/− mice did not, demonstrating that the sexually dimorphic role of osteocytic TGFβ signaling extends to the joint.…”

Section: Discussionmentioning

confidence: 99%

“…Mice. To assess the role of osteocytic TGFβ signaling in joint homeostasis, mice were bred to generate TβRII ocy−/− mice (DMP1-Cre + ; TβRII fl/fl ) and littermate control mice (DMP1-Cre − ; TβRII fl/fl ) (23,28). Animals were housed in groups in a pathogen-free facility at 22°C on a 12-hour light/dark cycle and supplied with standard irradiated mouse chow and water ad libitum.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously reported that male TβRII ocy−/− mice demonstrate osteocyte PLR suppression within the cortical femur, with reduced expression of several essential PLR enzymes and a corresponding reduction in canalicular length (23,28). We evaluated the effect of osteocyte-intrinsic TβRII-deficiency on canalicular length in subchondral bone.…”

Section: Requirement Of Osteocytic Tβrii For Subchondral Bone Canalicmentioning

confidence: 99%

“…During PLR, osteocytes secrete acid and proteases to dynamically resorb and then replace their surrounding bone matrix to maintain the mineral homeostasis, the canalicular network, and bone quality (24)(25)(26)(27). Osteocyte-intrinsic inhibition of TGFβ signaling causes PLR suppression, including disrupted canalicular networks, dysregulation of PLR enzyme expression, increased trabecular bone volume, and inferior bone quality in male, but not in female, mice (23,28). Thus, osteocytic TGFβ signaling functions to maintain both biologic and structural properties of bone, each of which could impact cartilage integrity.…”

Section: Introductionmentioning

confidence: 99%

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Mechanosensitive Control of Articular Cartilage and Subchondral Bone Homeostasis in Mice Requires Osteocytic Transforming Growth Factor β Signaling

Bailey

Nguyen

Yee

et al. 2021

Arthritis & Rheumatology

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Objective. Transforming growth factor β (TGFβ) signaling plays a complex tissue-specific and nonlinear role in osteoarthritis (OA). This study was conducted to determine the osteocytic contributions of TGFβ signaling to OA. Methods. To identify the role of osteocytic TGFβ signaling in joint homeostasis, we used 16-week-old male mice (n = 9-11 per group) and female mice (n = 7-11 per group) with an osteocyte-intrinsic ablation of TGFβ receptor type II (TβRII ocy−/− mice) and assessed defects in cartilage degeneration, subchondral bone plate (SBP) thickness, and SBP sclerostin expression. To further investigate these mechanisms in 16-week-old male mice, we perturbed joint homeostasis by subjecting 8-week-old mice to medial meniscal/ligamentous injury (MLI), which preferentially disrupts the mechanical environment of the medial joint to induce OA. Results. In all contexts, independent of sex, genotype, or medial or lateral joint compartment, increased SBP thickness and SBP sclerostin expression were spatially associated with cartilage degeneration. Male TβRII ocy−/− mice, but not female TβRII ocy−/− mice, had increased cartilage degeneration, increased SBP thickness, and higher levels of SBP sclerostin compared with control mice (all P < 0.05), demonstrating that the role of osteocytic TGFβ signaling on joint homeostasis is sexually dimorphic. With changes in joint mechanics following injury, control mice had increased SBP thickness, subchondral bone volume, and SBP sclerostin expression (all P < 0.05). TβRII ocy−/− mice, however, were insensitive to subchondral bone changes with injury, suggesting that mechanosensation at the SBP requires osteocytic TGFβ signaling. Conclusion. Our results provide new evidence that osteocytic TGFβ signaling is required for a mechanosensitive response to injury, and that osteocytes control SBP homeostasis to maintain cartilage health, identifying osteocytic TGFβ signaling as a novel therapeutic target for OA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Requirement Of Osteocytic Tβrii For Subchondral Bone Canalicmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mechanosensitive Control of Articular Cartilage and Subchondral Bone Homeostasis in Mice Requires Osteocytic Transforming Growth Factor β Signaling

Bailey

Nguyen

Yee

et al. 2021

Arthritis & Rheumatology

Self Cite

View full text Add to dashboard Cite

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Impact of Alcohol on Bone Health in People Living With HIV: Integrating Clinical Data From Serum Bone Markers With Morphometric Analysis in a Non‐Human Primate Model

et al. 2022

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People living with HIV (PLWH) represent a vulnerable population to adverse musculoskeletal outcomes due to HIV infection, antiretroviral therapy (ART), and at‐risk alcohol use. Developing measures to prevent skeletal degeneration in this group requires a grasp of the relationship between alcohol use and low bone mass in both the PLWH population and its constituents as defined by sex, age, and race. We examined the association of alcohol use with serum biochemical markers of bone health in a diverse cohort of PLWH enrolled in the New Orleans Alcohol Use in HIV (NOAH) study. To explore the effects of alcohol on bone in the context of HIV and ART and the role of estrogen, we conducted a parallel, translational study using simian immunodeficiency virus (SIV) + /ART + female rhesus macaques divided into four groups: vehicle (Veh)/Sham; chronic binge alcohol (CBA)/Sham; Veh/ovariectomy (OVX); and CBA/OVX. Clinical data showed that both osteocalcin (Ocn) and procollagen type I N‐propeptide (PINP) levels were inversely associated with multiple measures of alcohol consumption. Age (>50 years) significantly increased susceptibility to alcohol‐associated suppression of bone formation in both female and male PLWH, with postmenopausal status appearing as an additional risk factor in females. Serum sclerostin (Scl) levels correlated positively with measures of alcohol use and negatively with Ocn. Micro‐CT analysis of the macaque tibias revealed that although both CBA and OVX independently decreased trabecular number and bone mineral density, only OVX decreased trabecular bone volume fraction and impacted cortical geometry. The clinical data implicate circulating Scl in the pathogenesis of alcohol‐induced osteopenia and suggest that bone morphology can be significantly altered in the absence of net change in osteoblast function as measured by serum markers. Inclusion of sophisticated tools to evaluate skeletal strength in clinical populations will be essential to understand the impact of alcohol‐induced changes in bone microarchitecture. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) R47H Variant Causes Distinct Age- and Sex-Dependent Musculoskeletal Alterations in Mice

Essex

Huot

Deosthale

et al. 2020

Journal of Bone and Mineral Research

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Previous studies proposed the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a receptor expressed in myeloid cells including microglia in brain and osteoclasts in bone, as a link between brain and bone disease. The TREM2 R47H variant is a known risk factor for Alzheimer's disease (AD), the most common form of dementia. To investigate whether altered TREM2 signaling could contribute to bone and skeletal muscle loss, independently of central nervous system defects, we used mice globally hemizygous for the TREM2 R47H variant (TREM2R47H/+), which do not exhibit AD pathology, and wild‐type (WT) littermate control mice. Dxa/Piximus showed bone loss in female TREM2R47H/+ animals between 4 and 13 months of age and reduced cancellous and cortical bone (measured by micro‐computed tomography [μCT]) at 13 months, which stalled out by 20 months of age. In addition, they exhibited decreased femoral biomechanical properties measured by three‐point bending at 13 months of age, but not at 4 or 20 months. Male TREM2R47H/+ animals had decreased trabecular bone geometry but increased ultimate strain and failure force at 20 months of age versus WT. Only male TREM2R47H/+ osteoclasts differentiated more ex vivo after 7 days with receptor activator of nuclear factor κB ligand (RANKL)/macrophage colony‐stimulating factor (M‐CSF) compared to WT littermates. Yet, estrogen receptor alpha expression was higher in female and male TREM2R47H/+ osteoclasts compared to WT mice. However, female TREM2R47H/+ osteoclasts expressed less complement 3 (C3), an estrogen responsive element, and increased protein kinase B (Akt) activity, suggesting altered estrogen signaling in TREM2R47H/+ cells. Despite lower bone volume/strength in TREM2R47H/+ mice, skeletal muscle function measured by plantar flexion and muscle contractility was increased in 13‐month‐old female mutant mice. Overall, these data demonstrate that an AD‐associated TREM2 variant can alter bone and skeletal muscle strength in a sex‐dimorphic manner independent of central neuropathology, potentially mediated through changes in osteoclastic intracellular signaling. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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TGFβ regulation of perilacunar/canalicular remodeling is sexually dimorphic

Cited by 6 publications

References 71 publications

Mechanosensitive Control of Articular Cartilage and Subchondral Bone Homeostasis in Mice Requires Osteocytic Transforming Growth Factor β Signaling

Mechanosensitive Control of Articular Cartilage and Subchondral Bone Homeostasis in Mice Requires Osteocytic Transforming Growth Factor β Signaling

Impact of Alcohol on Bone Health in People Living With HIV: Integrating Clinical Data From Serum Bone Markers With Morphometric Analysis in a Non‐Human Primate Model

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) R47H Variant Causes Distinct Age- and Sex-Dependent Musculoskeletal Alterations in Mice

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