-
Endocrine Reviews Nov 2022More than 2.1 million age-related fractures occur in the United States annually, resulting in an immense socioeconomic burden. Importantly, the age-related deterioration... (Review)
Review
More than 2.1 million age-related fractures occur in the United States annually, resulting in an immense socioeconomic burden. Importantly, the age-related deterioration of bone structure is associated with impaired bone healing. Fracture healing is a dynamic process which can be divided into four stages. While the initial hematoma generates an inflammatory environment in which mesenchymal stem cells and macrophages orchestrate the framework for repair, angiogenesis and cartilage formation mark the second healing period. In the central region, endochondral ossification favors soft callus development while next to the fractured bony ends, intramembranous ossification directly forms woven bone. The third stage is characterized by removal and calcification of the endochondral cartilage. Finally, the chronic remodeling phase concludes the healing process. Impaired fracture healing due to aging is related to detrimental changes at the cellular level. Macrophages, osteocytes, and chondrocytes express markers of senescence, leading to reduced self-renewal and proliferative capacity. A prolonged phase of "inflammaging" results in an extended remodeling phase, characterized by a senescent microenvironment and deteriorating healing capacity. Although there is evidence that in the setting of injury, at least in some tissues, senescent cells may play a beneficial role in facilitating tissue repair, recent data demonstrate that clearing senescent cells enhances fracture repair. In this review, we summarize the physiological as well as pathological processes during fracture healing in endocrine disease and aging in order to establish a broad understanding of the biomechanical as well as molecular mechanisms involved in bone repair.
Topics: Humans; Fracture Healing; Bony Callus; Osteogenesis; Fractures, Bone; Cellular Senescence; Aging; Endocrine System Diseases
PubMed: 35182420
DOI: 10.1210/endrev/bnac008 -
The Journal of Clinical Investigation Apr 2022Cellular senescence plays an important role in human diseases, including osteoporosis and osteoarthritis. Senescent cells (SCs) produce the senescence-associated...
Cellular senescence plays an important role in human diseases, including osteoporosis and osteoarthritis. Senescent cells (SCs) produce the senescence-associated secretory phenotype to affect the function of neighboring cells and SCs themselves. Delayed fracture healing is common in the elderly and is accompanied by reduced mesenchymal progenitor cells (MPCs). However, the contribution of cellular senescence to fracture healing in the aged has not to our knowledge been studied. Here, we used C57BL/6J 4-month-old young and 20-month-old aged mice and demonstrated a rapid increase in SCs in the fracture callus of aged mice. The senolytic drugs dasatinib plus quercetin enhanced fracture healing in aged mice. Aged callus SCs inhibited the growth and proliferation of callus-derived MPCs (CaMPCs) and expressed high levels of TGF-β1. TGF-β-neutralizing Ab prevented the inhibitory effects of aged callus SCs on CaMPCs and promoted fracture healing in aged mice, which was associated with increased CaMPCs and proliferating cells. Thus, fracture triggered a significant cellular senescence in the callus cells of aged mice, which inhibited MPCs by expressing TGF-β1. Short-term administration of dasatinib plus quercetin depleted callus SCs and accelerated fracture healing in aged mice. Senolytic drugs represent a promising therapy, while TGF-β1 signaling is a molecular mechanism for fractures in the elderly via SCs.
Topics: Animals; Cellular Senescence; Dasatinib; Fracture Healing; Fractures, Bone; Mice; Mice, Inbred C57BL; Quercetin; Transforming Growth Factor beta1
PubMed: 35426372
DOI: 10.1172/JCI148073 -
Journal of Orthopaedic Translation Nov 2022Osteogenesis and angiogenesis are important for bone fracture healing. Irisin is a muscle-derived monokine that is associated with bone formation.
BACKGROUND
Osteogenesis and angiogenesis are important for bone fracture healing. Irisin is a muscle-derived monokine that is associated with bone formation.
METHODS
To demonstrate the effect of irisin on bone fracture healing, closed mid-diaphyseal femur fractures were produced in 8-week-old C57BL/6 mice. Irisin was administrated intraperitoneally every other day after surgery, fracture healing was assessed by using X-rays. Bone morphometry of the fracture callus were assessed by using micro-computed tomography. Femurs of mice from each group were assessed by the three-point bending testing. Effect of irisin on osteogenic differentiation in mesenchymal stem cells was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR), alkaline phosphatase staining and alizarin red staining. Angiogenesis of human umbilical vein endothelial cells (HUVECs) were evaluated by qRT-PCR, migration tests, and tube formation assays.
RESULTS
Increased callus formation, mineralization and tougher fracture healing were observed in the irisin-treated group than in the control group, indicating the better fracture callus healing due to Irisin treatment. The vessel surface and vessel volume fraction of the callus also increased in the irisin-treated group. The expression of BMP2, CD31, and VEGF in callus were enhanced in the irisin-treated group. In mouse bone mesenchymal stem cells, irisin promoted ALP expression and mineralization, and increased the expression of osteogenic genes, including , , , , and . Irisin also promoted HUVEC migration and tube formation. Expression of angiogenic genes, including , , , , , and in HUVECs were increased by irisin.
CONCLUSION
All the results indicate irisin can promote fracture healing through osteogenesis and angiogenesis. These findings help in the understanding of muscle-bone interactions during fracture healing.
THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE
Irisin was one of the most important monokine secreted by skeletal muscle. Studies have found that irisin have anabolic effect one bone remodeling through affecting osteocyte and osteoblast. Based on our study, irisin could promote bone fracture healing by increasing bone mass and vascularization, which provide a potential usage of irisin to promote fracture healing and improve clinical outcomes.
PubMed: 36196152
DOI: 10.1016/j.jot.2022.07.006 -
International Journal of Biological... 2022The biomechanical environment plays a dominant role in fracture healing, and Piezo1 is regarded as a major mechanosensor in bone homeostasis. However, the role of Piezo1...
The biomechanical environment plays a dominant role in fracture healing, and Piezo1 is regarded as a major mechanosensor in bone homeostasis. However, the role of Piezo1 in fracture healing is not yet well characterized. In this study, we first delineated that Piezo1 is highly expressed in periosteal stem cells (PSCs) and their derived osteoblastic lineage cells and chondrocytes. Furthermore, downregulation of Piezo1 in callus leads to impaired fracture healing, while activation by its specific agonist promotes fracture healing through stimulation of PSC-modulated chondrogenesis and osteogenesis, along with accelerated cartilage-to-bone transformation. Interestingly, vascular endothelial growth factor A is upregulated after Yoda1 treatment of PSCs, indicating an indirect role of Piezo1 in angiogenesis. Mechanistically, activation of Piezo1 promotes expression of Yes-associated protein (YAP) and its nuclear localization in PSCs, which in turn increases the expression and nuclear localization of β-catenin. In detail, YAP directly interacts with β-catenin in the nucleus and forms a transcriptional YAP/β-catenin complex, which upregulates osteogenic, chondrogenic and angiogenic factors. Lastly, Yoda1 treatment significantly improves fracture healing in a delayed union mouse model generated by tail suspension. These findings indicate that Piezo1 is a potential therapeutic target for fracture delayed union or nonunion.
Topics: Animals; Bony Callus; Fracture Healing; Ion Channels; Mice; Osteogenesis; Stem Cells; Vascular Endothelial Growth Factor A; beta Catenin
PubMed: 35844802
DOI: 10.7150/ijbs.71390 -
Signal Transduction and Targeted Therapy Jul 2023Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous...
Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous system (CNS) plays a pivotal role in regulating immune system and skeletal homeostasis. However, the impact of CNS injury on hematopoiesis commitment was overlooked. Here, we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing; chemical sympathectomy blocks TBI-induced fracture healing. TBI-induced hypersensitivity of adrenergic signaling promotes the proliferation of bone marrow hematopoietic stem cells (HSCs) and swiftly skews HSCs toward anti-inflammation myeloid cells within 14 days, which favor fracture healing. Knockout of β3- or β2-adrenergic receptor (AR) eliminate TBI-mediated anti-inflammation macrophage expansion and TBI-accelerated fracture healing. RNA sequencing of bone marrow cells revealed that Adrb2 and Adrb3 maintain proliferation and commitment of immune cells. Importantly, flow cytometry confirmed that deletion of β2-AR inhibits M2 polarization of macrophages at 7th day and 14th day; and TBI-induced HSCs proliferation was impaired in β3-AR knockout mice. Moreover, β3- and β2-AR agonists synergistically promote infiltration of M2 macrophages in callus and accelerate bone healing process. Thus, we conclude that TBI accelerates bone formation during early stage of fracture healing process by shaping the anti-inflammation environment in the bone marrow. These results implicate that the adrenergic signals could serve as potential targets for fracture management.
Topics: Mice; Animals; Fracture Healing; Bone Marrow; Myelopoiesis; Mice, Knockout; Brain Injuries, Traumatic; Adrenergic Agents
PubMed: 37402714
DOI: 10.1038/s41392-023-01457-w -
Deutsches Arzteblatt International Jun 2020Many people have leg-length discrepancies of greater or lesser severity. No evidence-based studies on the need for treatment are currently available.
BACKGROUND
Many people have leg-length discrepancies of greater or lesser severity. No evidence-based studies on the need for treatment are currently available.
METHODS
This review is based on publications retrieved by a selective search in the PubMed database, as well as on published recommendations from Germany and abroad and on the authors' own clinical experience.
RESULTS
If the two legs are of different lengths, this is generally because one leg is too short. It is debated whether leg-length discrepancy causes pain or long-term musculoskeletal disturbances. A direct connection to back pain is questionable, but a mildly elevated incidence of knee arthritis seems likely. The evidence base on the indications for treatment of leg-length discrepancy is poor; only informal consensus recommendations are available. There are a wide variety of conservative and surgical treatment options. The final extent of a leg-length discrepancy first noted during the growing years can be estimated with predictive algorithms to within 2 cm. The treatments that can be considered include a shoe insert, a high shoe, or an orthosis, surgically induced slowing of growth by blockade of the epiphyseal plates around the knee joint, or leg lengthening with osteotomy and subsequent distraction of the bone callus with fully implanted or external apparatus. Changes in leg length exert marked mechanical stress on the soft tissues. If the predicted leg-length discrepancy exceeds 5 cm, initial leg-lengthening treatment can already be considered during the patient's growing years.
CONCLUSION
It must be discussed with each patient individually whether the treatment should be conservative or surgical. The extent of the discrepancy is not the sole determining factor for the mode of treatment. The decision to treat is always elective.
Topics: Germany; Humans; Leg; Leg Length Inequality; Prostheses and Implants; Treatment Outcome
PubMed: 32865491
DOI: 10.3238/arztebl.2020.0405 -
Injury Jun 2021
Topics: Biomechanical Phenomena; Bony Callus; Fracture Healing; Humans
PubMed: 34099104
DOI: 10.1016/j.injury.2021.05.023 -
European Journal of Radiology Open 2020Periosteum is a fibrous sheath, coating the external bone, except in the articular surfaces, tendon insertions and sesamoid bone surface¹. It changes its aspects and...
Periosteum is a fibrous sheath, coating the external bone, except in the articular surfaces, tendon insertions and sesamoid bone surface¹. It changes its aspects and characteristics with aging, becoming progressively less elastic and more firm. It is composed of two different layers: outer fibrous (firm, collagen-filled) and inner proliferative (cambium, containing osteoprogenitor cells). Four vascular systems are responsible for the blood supply of the periosteum: the intrinsic periosteal system, located between fibrous and proliferative layer; the periosteocortical, the main nutritional arteries of the periosteum; the musculoperiosteal, responsible for the callus formation after fractures; the fascioperiosteal, specifically for each bone.³ It is crucial to bone formation and resorption, reacting to insults in the cortical bone, such as tumors, infections, traumas, medications and arthritic diseases. The aggressiveness of the reaction can be suggested by its radiological aspect and appearance. The periosteum in children is looser compared to adults, resulting in earlier and more exuberant reactions. All these aspects will be detailed, so the essential information all radiologists need to know will be discussed.
PubMed: 32923528
DOI: 10.1016/j.ejro.2020.100249 -
Angiogenesis Aug 2022Despite major research efforts to elucidate mechanisms of non-union formation, failed fracture healing remains a common complication in orthopedic surgery. Adequate... (Review)
Review
Despite major research efforts to elucidate mechanisms of non-union formation, failed fracture healing remains a common complication in orthopedic surgery. Adequate vascularization has been recognized as a crucial factor for successful bone regeneration, as newly formed microvessels guarantee the supply of the callus tissue with vital oxygen, nutrients, and growth factors. Accordingly, a vast number of preclinical studies have focused on the development of vascularization strategies to stimulate fracture repair. However, recent evidence suggests that stimulation of blood vessel formation is an oversimplified approach to support bone regeneration. This review discusses the role of vascularization during bone regeneration and delineates a phenomenon, for which we coin the term "the vascularization paradox of non-union-formation". This view is based on the results of a variety of experimental studies that suggest that the callus tissue of non-unions is indeed densely vascularized and that pro-angiogenic mediators, such as vascular endothelial growth factor, are sufficiently expressed at the facture site. By gaining further insights into the molecular and cellular basis of non-union vascularization, it may be possible to develop more optimized treatment approaches or even prevent the non-union formation in the future.
Topics: Bone Regeneration; Fracture Healing; Humans; Microvessels; Neovascularization, Pathologic; Neovascularization, Physiologic; Vascular Endothelial Growth Factor A
PubMed: 35165821
DOI: 10.1007/s10456-022-09832-x -
Current Osteoporosis Reports Jun 2020The clinical significance, target pathways, recent successes, and challenges that preclude translation of RNAi bone regenerative approaches are overviewed. (Review)
Review
PURPOSE OF REVIEW
The clinical significance, target pathways, recent successes, and challenges that preclude translation of RNAi bone regenerative approaches are overviewed.
RECENT FINDINGS
RNA interference (RNAi) is a promising new therapeutic approach for bone regeneration by stimulating or inhibiting critical signaling pathways. However, RNAi suffers from significant delivery challenges. These challenges include avoiding nuclease degradation, achieving bone tissue targeting, and reaching the cytoplasm for mRNA inhibition. Many drug delivery systems have overcome stability and intracellular localization challenges but suffer from protein adsorption that results in clearance of up to 99% of injected dosages, thus severely limiting drug delivery efficacy. While RNAi has myriad promising attributes for use in bone regenerative applications, delivery challenges continue to plague translation. Thus, a focus on drug delivery system development is critical to provide greater delivery efficiency and bone targeting to reap the promise of RNAi.
Topics: Bone Regeneration; Bony Callus; Drug Delivery Systems; Fracture Healing; Humans; MicroRNAs; Nanoparticles; RNA, Small Interfering; RNAi Therapeutics
PubMed: 32394316
DOI: 10.1007/s11914-020-00587-2