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1.
Curr Osteoporos Rep ; 21(5): 540-551, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37542684

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to summarize the recently published scientific literature regarding the effects of mitochondrial function and mitochondrial genome mutations on bone phenotype and aging. RECENT FINDINGS: While aging and sex steroid levels have traditionally been considered the most important risk factors for development of osteoporosis, mitochondrial function and genetics are being increasingly recognized as important determinants of bone health. Recent studies indicate that mitochondrial genome variants found in different human populations determine the risk of complex degenerative diseases. We propose that osteoporosis should be among such diseases. Studies have shown the deleterious effects of mitochondrial DNA mutations and mitochondrial dysfunction on bone homeostasis. Mediators of such effects include oxidative stress, mitochondrial permeability transition, and dysregulation of autophagy. Mitochondrial health plays an important role in bone homeostasis and aging, and understanding underlying mechanisms is critical in leveraging this relationship clinically for therapeutic benefit.


Assuntos
DNA Mitocondrial , Osteoporose , Humanos , DNA Mitocondrial/genética , Envelhecimento/genética , Mitocôndrias/genética , Mutação/genética , Osteoporose/genética , Fenótipo
2.
Bone ; 189: 117258, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39299628

RESUMO

Mitochondrial Permeability Transition Pore (MPTP) and its key positive regulator, Cyclophilin D (CypD), control activity of cell oxidative metabolism important for differentiation of stem cells of various lineages including osteogenic lineage. Our previous work (Sautchuk et al., 2022) showed that CypD gene, Ppif, is transcriptionally repressed during osteogenic differentiation by regulatory Smad transcription factors in BMP canonical pathway, a major driver of osteoblast (OB) differentiation. Such a repression favors closure of the MPTP, priming OBs to higher usage of mitochondrial oxidative metabolism. The physiological role of CypD/MPTP regulation was demonstrated by its inverse correlation with BMP signaling in aging and bone fracture healing in addition to the negative effect of CypD gain-of-function (GOF) on bone maintenance. Here we show evidence that CypD GOF also negatively affects bone development and growth as well as fracture healing in adult mice. Developing craniofacial and long bones presented with delayed ossification and decreased growth rate, respectively, whereas in fracture, bony callus volume was diminished. Given that Genome Wide Association Studies showed that PPIF locus is associated with both body height and bone mineral density, our new data provide functional evidence for the role of PPIF gene product, CypD, and thus MPTP in bone growth and repair.


Assuntos
Desenvolvimento Ósseo , Consolidação da Fratura , Peptidil-Prolil Isomerase F , Animais , Peptidil-Prolil Isomerase F/metabolismo , Peptidil-Prolil Isomerase F/genética , Consolidação da Fratura/fisiologia , Desenvolvimento Ósseo/fisiologia , Camundongos , Osteogênese/genética , Osteogênese/fisiologia , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Osteoblastos/metabolismo , Camundongos Endogâmicos C57BL , Ciclofilinas/metabolismo , Ciclofilinas/genética , Mitocôndrias/metabolismo
3.
Arthritis Rheumatol ; 75(6): 923-936, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36625730

RESUMO

OBJECTIVE: The synovial lymphatic system (SLS) removes catabolic factors from the joint. Vascular endothelial growth factor C (VEGF-C) and its receptor, VEGFR-3, are crucial for lymphangiogenesis. However, their involvement in age-related osteoarthritis (OA) is unknown. This study was undertaken to determine whether the SLS and the VEGF-C/VEGFR-3 pathway contribute to the development and progression of age-related OA, using a murine model of naturally occurring joint disease. METHODS: SLS function was assessed in the knees of young (3-month-old) and aged (19-24-month-old) male and female C57BL/6J mice via a newly established in vivo IVIS-dextran imaging approach, which, in addition to histology, was used to assess the effects of VEGF-C treatment on SLS function and OA pathology in aged mice. RNA-sequencing of synovial tissue was performed to explore molecular mechanisms of the disease in the mouse knee joints. RESULTS: Results showed that aged mice had impaired SLS function, including decreases in joint clearance (mean T1/2 of signal intensity clearance, 2.8 hours in aged mice versus 0.5 hours in young mice; P < 0.0001), synovial influx (mean ± SD 1.7 ± 0.8% in aged mice versus 4.1 ± 1.9% in young mice; P = 0.0004), and lymph node draining capacity (mean ± SD epifluorescence total radiant intensity ([photons/second]/[µW/cm2 ]) 1.4 ± 0.8 in aged mice versus 3.7 ± 1.2 in young mice; P < 0.0001). RNA-sequencing of the synovial tissue showed that Vegf-c and Vegfr3 signaling genes were decreased in the synovium of aged mice. VEGF-C treatment resulted in improvements in SLS function in aged mice, including increased percentage of signal intensity joint clearance (mean ± SD 63 ± 9% in VEGF-C-treated aged mice versus 52 ± 15% in vehicle-treated aged mice; P = 0.012), increased total articular cartilage cross-sectional area (mean ± SD 0.38 ± 0.07 mm2 in VEGF-C-treated aged mice versus 0.26 ± 0.07 mm2 in vehicle-treated aged mice; P < 0.0001), and decreased percentage of matrix metallopeptidase 13-positive staining area within total synovial area in 22-month-old VEGF-C-treated mice versus 22-month-old vehicle-treated mice (mean ± SD decrease 7 ± 2% versus 4 ± 1%; P = 0.0004). CONCLUSION: SLS function is reduced in the knee joints of aged mice due to decreased VEGF-C/VEGFR-3 signaling. VEGF-C treatment attenuates OA joint damage and improves synovial lymphatic drainage in aged mice. The SLS and VEGF-C/VEGFR-3 signaling represent novel physiopathologic mechanisms that could potentially be used as therapeutic targets for age-related OA.


Assuntos
Osteoartrite , Fator C de Crescimento do Endotélio Vascular , Camundongos , Masculino , Feminino , Animais , Receptor 3 de Fatores de Crescimento do Endotélio Vascular , Camundongos Endogâmicos C57BL , Osteoartrite/metabolismo , Membrana Sinovial/metabolismo , RNA/metabolismo
4.
J Bone Miner Res ; 36(7): 1387-1402, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33724538

RESUMO

The growth plates are key engines of skeletal development and growth and contain a top reserve zone followed by maturation zones of proliferating, prehypertrophic, and hypertrophic/mineralizing chondrocytes. Trauma or drug treatment of certain disorders can derange the growth plates and cause accelerated maturation and premature closure, one example being anti-hedgehog drugs such as LDE225 (Sonidegib) used against pediatric brain malignancies. Here we tested whether such acceleration and closure in LDE225-treated mice could be prevented by co-administration of a selective retinoid antagonist, based on previous studies showing that retinoid antagonists can slow down chondrocyte maturation rates. Treatment of juvenile mice with an experimental dose of LDE225 for 2 days (100 mg/kg by gavage) initially caused a significant shortening of long bone growth plates, with concomitant decreases in chondrocyte proliferation; expression of Indian hedgehog, Sox9, and other key genes; and surprisingly, the number of reserve progenitors. Growth plate involution followed with time, leading to impaired long bone lengthening. Mechanistically, LDE225 treatment markedly decreased the expression of retinoid catabolic enzyme Cyp26b1 within growth plate, whereas it increased and broadened the expression of retinoid synthesizing enzyme Raldh3, thus subverting normal homeostatic retinoid circuitries and in turn accelerating maturation and closure. All such severe skeletal and molecular changes were prevented when LDE-treated mice were co-administered the selective retinoid antagonist CD2665 (1.5 mg/kg/d), a drug targeting retinoid acid receptor γ, which is most abundantly expressed in growth plate. When given alone, CD2665 elicited the expected maturation delay and growth plate expansion. In vitro data showed that LDE225 acted directly to dampen chondrogenic phenotypic expression, a response fully reversed by CD2665 co-treatment. In sum, our proof-of-principle data indicate that drug-induced premature growth plate closures can be prevented or delayed by targeting a separate phenotypic regulatory mechanism in chondrocytes. The translation applicability of the findings remains to be studied. © 2021 American Society for Bone and Mineral Research (ASBMR).


Assuntos
Antineoplásicos , Neoplasias , Animais , Diferenciação Celular , Criança , Condrócitos , Lâmina de Crescimento , Proteínas Hedgehog , Humanos , Camundongos , Retinoides
5.
Sci Signal ; 14(669)2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33563697

RESUMO

Heterotopic ossification (HO) is a common, potentially debilitating pathology that is instigated by inflammation caused by tissue damage or other insults, which is followed by chondrogenesis, osteogenesis, and extraskeletal bone accumulation. Current remedies are not very effective and have side effects, including the risk of triggering additional HO. The TGF-ß family member activin A is produced by activated macrophages and other inflammatory cells and stimulates the intracellular effectors SMAD2 and SMAD3 (SMAD2/3). Because HO starts with inflammation and because SMAD2/3 activation is chondrogenic, we tested whether activin A stimulated HO development. Using mouse models of acquired intramuscular and subdermal HO, we found that blockage of endogenous activin A by a systemically administered neutralizing antibody reduced HO development and bone accumulation. Single-cell RNA-seq analysis and developmental trajectories showed that the antibody treatment reduced the recruitment of Sox9+ skeletal progenitors, many of which also expressed the gene encoding activin A (Inhba), to HO sites. Gain-of-function assays showed that activin A enhanced the chondrogenic differentiation of progenitor cells through SMAD2/3 signaling, and inclusion of activin A in HO-inducing implants enhanced HO development in vivo. Together, our data reveal that activin A is a critical upstream signaling stimulator of acquired HO in mice and could represent an effective therapeutic target against forms of this pathology in patients.


Assuntos
Miosite Ossificante , Ossificação Heterotópica , Ativinas/genética , Animais , Condrogênese , Camundongos , Ossificação Heterotópica/genética , Osteogênese
6.
Sci Signal ; 14(701): eabf3535, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34546791

RESUMO

Canonical nuclear factor κB (NF-κB) signaling mediated by homo- and heterodimers of the NF-κB subunits p65 (RELA) and p50 (NFKB1) is associated with age-related pathologies and with disease progression in posttraumatic models of osteoarthritis (OA). Here, we established that NF-κB signaling in articular chondrocytes increased with age, concomitant with the onset of spontaneous OA in wild-type mice. Chondrocyte-specific expression of a constitutively active form of inhibitor of κB kinase ß (IKKß) in young adult mice accelerated the onset of the OA-like phenotype observed in aging wild-type mice, including degenerative changes in the articular cartilage, synovium, and menisci. Both in vitro and in vivo, chondrocytes expressing activated IKKß had a proinflammatory secretory phenotype characterized by markers typically associated with the senescence-associated secretory phenotype (SASP). Expression of these factors was differentially regulated by p65, which contains a transactivation domain, and p50, which does not. Whereas the loss of p65 blocked the induction of genes encoding SASP factors in chondrogenic cells treated with interleukin-1ß (IL-1ß) in vitro, the loss of p50 enhanced the IL-1ß­induced expression of some SASP factors. The loss of p50 further exacerbated cartilage degeneration in mice with chondrocyte-specific IKKß activation. Overall, our data reveal that IKKß-mediated activation of p65 can promote OA onset and that p50 may limit cartilage degeneration in settings of joint inflammation including advanced age.


Assuntos
NF-kappa B , Osteoartrite , Animais , Condrócitos/metabolismo , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Osteoartrite/genética , Transdução de Sinais
7.
J Bone Miner Res ; 34(9): 1676-1689, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31189030

RESUMO

RUNX2 is a transcription factor critical for chondrocyte maturation and normal endochondral bone formation. It promotes the expression of factors catabolic to the cartilage extracellular matrix and is upregulated in human osteoarthritic cartilage and in murine articular cartilage following joint injury. To date, in vivo studies of RUNX2 overexpression in cartilage have been limited to forced expression in osteochondroprogenitor cells preventing investigation into the effects of chondrocyte-specific RUNX2 overexpression in postnatal articular cartilage. Here, we used the Rosa26Runx2 allele in combination with the inducible Col2a1CreERT2 transgene or the inducible AcanCreERT2 knock-in allele to achieve chondrocyte-specific RUNX2 overexpression (OE) during embryonic development or in the articular cartilage of adult mice, respectively. RUNX2 OE was induced at embryonic day 13.5 (E13.5) for all developmental studies. Histology and in situ hybridization analyses suggest an early onset of chondrocyte hypertrophy and accelerated terminal maturation in the limbs of the RUNX2 OE embryos compared to control embryos. For all postnatal studies, RUNX2 OE was induced at 2 months of age. Surprisingly, no histopathological signs of cartilage degeneration were observed even 6 months following induction of RUNX2 OE. Using the meniscal/ligamentous injury (MLI), a surgical model of knee joint destabilization and meniscal injury, however, we found that RUNX2 OE accelerates the progression of cartilage degeneration following joint trauma. One month following MLI, the numbers of MMP13-positive and TUNEL-positive chondrocytes were significantly greater in the articular cartilage of the RUNX2 OE joints compared to control joints and 2 months following MLI, histomorphometry and Osteoarthritis Research Society International (OARSI) scoring revealed decreased cartilage area in the RUNX2 OE joints. Collectively, these results suggest that although RUNX2 overexpression alone may not be sufficient to initiate the OA degenerative process, it may predetermine the rate of OA onset and/or progression following traumatic joint injury. © 2019 American Society for Bone and Mineral Research.


Assuntos
Envelhecimento/patologia , Condrócitos/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Progressão da Doença , Osteoartrite/etiologia , Osteoartrite/metabolismo , Ferimentos e Lesões/complicações , Animais , Animais Recém-Nascidos , Cartilagem Articular/patologia , Condrócitos/patologia , Feminino , Humanos , Articulação do Joelho/patologia , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Especificidade de Órgãos , Osteocondrodisplasias/patologia , Fenótipo
8.
PLoS One ; 12(4): e0174705, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28384173

RESUMO

Osteoarthritis (OA) is a degenerative joint disease for which there are no disease modifying therapies. Thus, strategies that offer chondroprotective or regenerative capability represent a critical unmet need. Recently, oral consumption of a hydrolyzed type 1 collagen (hCol1) preparation has been reported to reduce pain in human OA and support a positive influence on chondrocyte function. To evaluate the tissue and cellular basis for these effects, we examined the impact of orally administered hCol1 in a model of posttraumatic OA (PTOA). In addition to standard chow, male C57BL/6J mice were provided a daily oral dietary supplement of hCol1 and a meniscal-ligamentous injury was induced on the right knee. At various time points post-injury, hydroxyproline (hProline) assays were performed on blood samples to confirm hCol1 delivery, and joints were harvested for tissue and molecular analyses were performed, including histomorphometry, OARSI and synovial scoring, immunohistochemistry and mRNA expression studies. Confirming ingestion of the supplements, serum hProline levels were elevated in experimental mice administered hCol1. In the hCol1 supplemented mice, chondroprotective effects were observed in injured knee joints, with dose-dependent increases in cartilage area, chondrocyte number and proteoglycan matrix at 3 and 12 weeks post-injury. Preservation of cartilage and increased chondrocyte numbers correlated with reductions in MMP13 protein levels and apoptosis, respectively. Supplemented mice also displayed reduced synovial hyperplasia that paralleled a reduction in Tnf mRNA, suggesting an anti-inflammatory effect. These findings establish that in the context of murine knee PTOA, daily oral consumption of hCol1 is chondroprotective, anti-apoptotic in articular chondrocytes, and anti-inflammatory. While the underlying mechanism driving these effects is yet to be determined, these findings provide the first tissue and cellular level information explaining the already published evidence of symptom relief supported by hCol1 in human knee OA. These results suggest that oral consumption of hCol1 is disease modifying in the context of PTOA.


Assuntos
Cartilagem Articular/metabolismo , Colágeno Tipo I/administração & dosagem , Suplementos Nutricionais , Modelos Animais de Doenças , Osteoartrite/metabolismo , Ferimentos e Lesões/complicações , Administração Oral , Animais , Hidrólise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoartrite/etiologia , Osteoartrite/prevenção & controle
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