Endosteal Bone Formation Research Articles

Distraction osteogenesis in combined sequential use of external fixation and nailing (lengthening and then nailing): An experimental study in rabbits.

Limb lengthening relies on the process of distraction osteogenesis. The active periosteal bone formation has been detected in clinical practice with a lengthening and then nail (LATN) technique but has not been confirmed by experimental studies to date. The aim of this study is to compare the tissue regeneration of the distraction regenerate during tibial lengthening in rabbits using a LATN technique. This study was performed on 54 mature rabbits of the Soviet Chinchilla breed, which were divided into three groups of 18 animals. In group 1 (control), the tibia was lengthened in an external fixator. In group 2, the LATN technique was modeled and in group 3, lengthening over nail (LON) was modeled. The total duration of the experiment was 45 days. On the 10th, 15th, 20th, 30th, and 45th day X-ray, computed tomography and morphological studies were performed. In the experimental groups (2 and 3), a more pronounced periosteal bone formation in the area of regenerate was noted when compared to group 1. In group 2 (LATN), wide cortical plates were formed from the intermediate and periosteal areas. In this group, the maximum densitometric density values were noted. Endosteal bone formation was preserved in all groups. The LON and LATN techniques, when compared with the classical Ilizarov lengthening, do not demonstrate any deficiency in the tissue regeneration of the bone tissue at the regenerate sites. The most powerful bone structures are formed with the sequential use of the external fixation and nailing (LATN).

Hydroxyapatite-Coated Femoral Stems in Primary Total Hip Arthroplasty: An Updated Meta-Analysis

BackgroundMost primary total hip arthroplasties (THAs) performed in the United States utilize cementless fixation with porous or hydroxyapatite (HA) coating. A previous meta-analysis comparing HA-coated versus non–HA-coated stems in primary THA published in 2013 found no significant difference between the 2. However, an updated analysis of the current literature is needed to assess the potential benefit of HA-coated stems in primary THA. MethodsVarious libraries were searched through May 2022 according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Studies included were randomized controlled trials comparing HA-coated femoral stems to non–HA-coated stems in primary THA. Outcomes included Harris Hip Score (HHS), endosteal bone formation, radiolucent lines, linear wear rate, revision for aseptic loosening, thigh pain, and heterotopic ossification. ResultsThere were significantly fewer revisions for aseptic loosening (P = .004) and decreased postoperative thigh pain (P = .03) for patients who have with HA-coated stems. There was no significant difference in HHS (P = .20), endosteal bone formation (P = .96), radiolucent lines (P = .75), linear wear rate (P = .41), or heterotopic ossification (P = .71) between HA-coated and non–HA-coated stems. ConclusionWe found that HA-coated femoral stems in primary THA led to significantly fewer stem revisions for aseptic loosening and less postoperative thigh pain compared to non–HA-coated stems. These findings suggest HA-coated femoral stems should be preferred over non–HA-coated femoral stems in primary THA.

Constitutive bone marrow adipocytes suppress local bone formation.

BM adipocytes (BMAd) are a unique cell population derived from BM 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 nonmarrow adipocytes or by BM 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 it 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.

Osteocytes regulate bone anabolic response to mechanical loading in male mice via activation of integrin α5

Physical mechanical stimulation can maintain and even increase bone mass. Here, we report an important role of osteocytic integrin α5 in regulating the anabolic response of bone to mechanical loading using an Itga5 conditional gene knockout (cKO) mouse model. Integrin α5 gene deletion increased apoptotic osteocytes and reduced cortical anabolic responses to tibial compression including decreased endosteal osteoblasts and bone formation, and increased endosteal osteoclasts and bone resorption, contributing to the decreased bone area fraction and biomechanical properties, leading to an enlarged bone marrow area in cKO mice. Similar disruption of anabolic responses to mechanical loading was also detected in cKO trabecular bone. Moreover, integrin α5 deficiency impeded load-induced Cx43 hemichannel opening, and production and release of PGE2, an anabolic factor, resulting in attenuated effects of the loading on catabolic sclerostin (SOST) reduction and anabolic β-catenin increase. Together, this study shows an indispensable role of integrin α5 in osteocytes in the anabolic action of mechanical loading on skeletal tissue through activation of hemichannels and PGE2-evoked gene expression. Integrin α5 could act as a potential new therapeutic target for bone loss, especially in the elderly population with impeded mechanical sensitivity.

Connexin hemichannels with prostaglandin release in anabolic function of bone to mechanical loading.

Mechanical stimulation, such as physical exercise, is essential for bone formation and health. Here, we demonstrate the critical role of osteocytic Cx43 hemichannels in anabolic function of bone in response to mechanical loading. Two transgenic mouse models, R76W and Δ130-136, expressing dominant-negative Cx43 mutants in osteocytes were adopted. Mechanical loading of tibial bone increased cortical bone mass and mechanical properties in wild-type and gap junction-impaired R76W mice through increased PGE2, endosteal osteoblast activity, and decreased sclerostin. These anabolic responses were impeded in gap junction/hemichannel-impaired Δ130-136 mice and accompanied by increased endosteal osteoclast activity. Specific inhibition of Cx43 hemichannels by Cx43(M1) antibody suppressed PGE2 secretion and impeded loading-induced endosteal osteoblast activity, bone formation and anabolic gene expression. PGE2 administration rescued the osteogenic response to mechanical loading impeded by impaired hemichannels. Together, osteocytic Cx43 hemichannels could be a potential new therapeutic target for treating bone loss and osteoporosis.

Distraction Osteogenesis in the Combined and Sequential Use of Transosseous and Intramedullary Osteosynthesis: Experimental Study

Background. The methods of “lengthening over the nail” (LON) and the sequential use of the external fixation and nailing in the option “lengthening and then the nail” (LATN) are characterized by ignoring non-observance of the formulated by G.A. Ilizarov is the most important condition for optimizing the osteogenesis process, namely, the preservation of medullary blood supply and osteogenic bone marrow tissue. At the same time, in clinical practice, there was no negative effect of the intramedullary nail on the formation of the regenerate. In experimental studies, the activation of periosteal bone formation during LON is noted. But the active periosteal bone formation detected in clinical practice with a sequential technique has not been confirmed by experimental studies.The aim of the study was to compare the organotypical rebuilding of the distraction regenerate during tibial lengthening in rabbits according to Ilizarov, over the intramedullary fixator and with the sequential use of the external fixation and nailing.Materials and Methods. The study was carried out on 54 mature rabbits of the Soviet Chinchilla breed, which were divided into 3 groups of 18 animals. In Gr-1 (control), the tibia was lengthened by 1 cm in a mini-Ilizarov apparatus at a rate of 1 mm per day for 4 sessions step. In Gr-2, the LATN technique was modeled. After the end of lengthening, an intramedullary fixator was implanted installed, the apparatus with the presence of wires only in the base supports was kept as an imitation of blocking the intramedullary fixator. In Gr-3, lengthening was performed over the intramedullary fixator; at the end of lengthening, the wires were left only in the base supports. The fixation period was is 30 days. The total duration of the experiment is 45 days. On the 10th, 15th, 20th, 30th, 45th day X-ray, CT and morphological studies were performed during the experiment.Results. In the experimental groups, a more pronounced periosteal bone formation in the area of regenerates was noted, while in Gr-3 (LON) cortical plates were formed mainly from the periosteal component, and in Gr-2 (LATN) wide cortical plates were formed from the intermediate and periosteal areas. In this group, the maximum densitometric density values are noted. Endosteal bone formation was preserved in all groups.Conclusion. The LON and LATN techniques, when compared with the classical Ilizarov lengthening, do not demonstrate any deficiency in the organotypical rebuilding of the bone tissue of the regenerates. All zones of bone formation are present, including endosteal, with intense periosteal bone formation. The most powerful bone structures are formed with the sequential use of the external fixation and nailing (LATN) in the form of the formation of wide cortical plates due to the intermediate and periosteal zones of the regenerate.

Loss of Adenylyl Cyclase 6 in Leptin Receptor-Expressing Stromal Cells Attenuates Loading-Induced Endosteal Bone Formation.

ABSTRACTBone marrow stromal/stem cells represent a quiescent cell population that replenish the osteoblast bone‐forming cell pool with age and in response to injury, maintaining bone mass and repair. A potent mediator of stromal/stem cell differentiation in vitro and bone formation in vivo is physical loading, yet it still remains unclear whether loading‐induced bone formation requires the osteogenic differentiation of these resident stromal/stem cells. Therefore, in this study, we utilized the leptin receptor (LepR) to identify and trace the contribution of bone marrow stromal cells to mechanoadaptation of bone in vivo. Twelve‐week‐old Lepr‐cre;tdTomato mice were subjected to compressive tibia loading with an 11 N peak load for 40 cycles, every other day for 2 weeks. Histological analysis revealed that Lepr‐cre;tdTomato+ cells arise perinatally around blood vessels and populate bone surfaces as lining cells or osteoblasts before a percentage undergo osteocytogenesis. Lepr‐cre;tdTomato+ stromal cells within the marrow increase in abundance with age, but not following the application of tibial compressive loading. Mechanical loading induces an increase in bone mass and bone formation parameters, yet does not evoke an increase in Lepr‐cre;tdTomato+ osteoblasts or osteocytes. To investigate whether adenylyl cyclase‐6 (AC6) in LepR cells contributes to this mechanoadaptive response, Lepr‐cre;tdTomato mice were further crossed with AC6fl/fl mice to generate a LepR+ cell‐specific knockout of AC6. These Lepr‐cre;tdTomato;AC6 fl/fl animals have an attenuated response to compressive tibia loading, characterized by a deficient load‐induced osteogenic response on the endosteal bone surface. This, therefore, shows that Lepr‐cre;tdTomato+ cells contribute to short‐term bone mechanoadaptation. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Effect of chitosan and Dysphania ambrosioides on the bone regeneration process: A randomized controlled trial in an animal model.

The focus of this triple-blind study was on evaluating the effect of chitosan combined with Dysphania ambrosioides (A) extract on the bone repair process in vivo. In total, 60 male Wistar rats (Rattus norvegicus albinus) weighing between 260 and 270 g were randomly selected for this study and distributed into four groups (n = 15). Group C (chitosan), Group CA5 (chitosan + 5% of D. ambrosioides), Group CA20 (chitosan + 20% of D. ambrosioides), and Group CO (Control-Blood clot). In each animal, bone defects measuring 2 mm in diameter were performed in both tibias for placement of the substances. After 7, 15, and 30 days, the animals were sedated and sacrificed using the cervical dislocation technique and the tissues were analyzed under optical microscope relative to the following events: inflammatory infiltrate, necrosis, osteoclasts, osteoblasts, fibroblasts, periosteal, and endosteal bone formation. The data were evaluated to verify distribution using the Kolmogorov-Smirnov test, and variance, using the Levene test; as distribution was not normal, data were subjected to the Kruskal-Wallis and Dunn nonparametric tests (p < .05). A significant inflammatory infiltrate was observed in Group CA5 (p = .008) in the time interval of 7 days, and in Group C at 15 (p = .009) and 30 (p = .017) days. Osteoblastic activity was more significant in Group CA20 (p = .027) compared with CA5 in the time interval of 7 days. Group CA20 demonstrated a significantly higher endosteal and periosteal bone formation value in the time interval of 7 (p = .013), 15 (p = .004), and 30 days (p = .008) compared with the other groups. The null hypothesis was refuted, bone regeneration was faster in spheres with an association of chitosan and 20% extract, and complete bone repair occurred clinically at 15 days and histologically at 30 days. The spheres proved to be a promising method for the biostimulation of alveolar bone repair and bone fractures.

Inducible expression of Wnt7b promotes bone formation in aged mice and enhances fracture healing

There remain unmet clinical needs for safe and effective bone anabolic therapies to treat aging-related osteoporosis and to improve fracture healing in cases of nonunion or delayed union. Wnt signaling has emerged as a promising target pathway for developing novel bone anabolic drugs. Although neutralizing antibodies against the Wnt antagonist sclerostin have been tested, Wnt ligands themselves have not been fully explored as a potential therapy. Previous work has demonstrated Wnt7b as an endogenous ligand upregulated during osteoblast differentiation, and that Wnt7b overexpression potently stimulates bone accrual in the mouse. The earlier studies however did not address whether Wnt7b could promote bone formation when specifically applied to aged or fractured bones. Here we have developed a doxycycline-inducible strategy where Wnt7b is temporally induced in the bones of aged mice or during fracture healing. We report that forced expression of Wnt7b for 1 month starting at 15 months of age greatly stimulated trabecular and endosteal bone formation, resulting in a marked increase in bone mass. We further tested the effect of Wnt7b on bone healing in a murine closed femur fracture model. Induced expression of Wnt7b at the onset of fracture did not affect the initial cartilage formation but promoted mineralization of the subsequent bone callus. Thus, targeted delivery of Wnt7b to aged bones or fracture sites may be explored as a potential therapy.

Stroke Prevents Exercise-Induced Gains in Bone Microstructure But Not Composition in Mice.

Ischemic stroke induces rapid loss in bone mineral density that is up to 13 times greater than during normal aging, leading to a markedly increased risk of fracture. Little is known about skeletal changes following stroke beyond density loss. In this study, we use a mild-moderate middle cerebral artery occlusion model to determine the effects of ischemic stroke without bedrest on bone microstructure, dynamic bone formation, and tissue composition. Twenty-seven 12-week-old male C57Bl/6J mice received either a stroke or sham surgery and then either received daily treadmill exercise or remained sedentary for 4 weeks. All mice were ambulatory immediately following stroke, and limb coordination during treadmill exercise was unaffected by stroke, indicating similar mechanical loading across limbs for both stroke and sham groups. Stroke did not directly detriment microstructure, but exercise only stimulated adaptation in the sham group, not the stroke group, with increased bone volume fraction and trabecular thickness in the sham distal femoral metaphysis. Stroke differentially decreased cortical area in the distal femoral metaphysis for the affected limb relative to the unaffected limb, as well as endosteal bone formation rate in the affected tibial diaphysis. Although exercise failed to improve bone microstructure following stroke, exercise increased mineral-to-matrix content in stroke but not sham. Together, these results show that stroke inhibits exercise-induced changes to femoral microstructure but not tibial composition, even without changes to gait. Similarly, affected-unaffected limb differences in cortical bone structure and bone formation rate in ambulatory mice show that stroke affects bone health even without bedrest.

Sfrp4 repression of the Ror2/Jnk cascade in osteoclasts protects cortical bone from excessive endosteal resorption

Loss-of-function mutations in the Wnt inhibitor secreted frizzled receptor protein 4 (SFRP4) cause Pyle's disease (OMIM 265900), a rare skeletal disorder characterized by wide metaphyses, significant thinning of cortical bone, and fragility fractures. In mice, we have shown that the cortical thinning seen in the absence of Sfrp4 is associated with decreased periosteal and endosteal bone formation and increased endocortical resorption. While the increase in Rankl/Opg in cortical bone of mice lacking Sfrp4 suggests an osteoblast-dependent effect on endocortical osteoclast (OC) activity, whether Sfrp4 can cell-autonomously affect OCs is not known. We found that Sfrp4 is expressed during bone marrow macrophage OC differentiation and that Sfrp4 significantly suppresses the ability of early and late OC precursors to respond to Rankl-induced OC differentiation. Sfrp4 deletion in OCs resulted in activation of canonical Wnt/β-catenin and noncanonical Wnt/Ror2/Jnk signaling cascades. However, while inhibition of canonical Wnt/β-catenin signaling did not alter the effect of Sfrp4 on OCgenesis, blocking the noncanonical Wnt/Ror2/Jnk cascade markedly suppressed its regulation of OC differentiation in vitro. Importantly, we report that deletion of Ror2 exclusively in OCs (CtskCreRor2fl/fl ) in Sfrp4 null mice significantly reversed the increased number of endosteal OCs seen in these mice and reduced their cortical thinning. Altogether, these data show autocrine and paracrine effects of Sfrp4 in regulating OCgenesis and demonstrate that the increase in endosteal OCs seen in Sfrp4-/- mice is a consequence of noncanonical Wnt/Ror2/Jnk signaling activation in OCs overriding the negative effect that activation of canonical Wnt/β-catenin signaling has on OCgenesis.

Mechanical Loading Shows Anti-Myeloma Effects While Rescuing Bone Loss with Net Bone Formation in a Myeloma Bone Disease Murine Model

Osteolytic bone disease (BD) is a hallmark of multiple myeloma (MM) with tumor cells in the bone marrow shifting the balance of the bone remodeling process towards massive bone resorption. As a result, patients develop devastating osteolytic lesions that lead to non-healing bone fractures and pain, affecting life quality and mortality rates. Bones have the capacity to adapt mass and structure to mechanical stimuli, as dramatically seen in young tennis athletes with muscle-bone asymmetries in the playing arm. We have previously shown that tibial mechanical loading rescued bone loss in our murine MOPC315.BM MM model with an advanced osteolytic phenotype. Here, we hypothesize that mechanical strain (1) modulates the bone microenvironment and (2) has antitumor activity in mice. (1) We determined bone formation and bone resorption parameters by time-lapsed microCT analysis to show how skeletal mechanical stimuli control MM bone disease (MMBD) progression over time. (2) To monitor tumor progression, we used non-invasive bioluminescence imaging (BLI) and enzyme-linked immunosorbent assay (ELISA) for detection of MOPC315.BM specific immunoglobulin A (IgA) levels. In our in vivo loading study, we injected MOPC315.BM cells intratibially (i.t.) in BALB/c mice to establish MMBD (n=17) and used PBS-injected (n=13) as well as noninjected mice (n=8) as controls. Eight (MM), seven (PBS) and 8 (noninjected) mice received compressive tibial loading for three weeks while nine (MM) and six (PBS) mice served as nonloaded controls. The bone remodeling response to mechanical loading was investigated by longitudinal in vivo microCT imaging performed every 5 days (at day 13, 18, 23, 28, and 33 after i.t. injection). MicroCT images from day 33 were geometrically registered onto images of day 13 and resampled into the same coordinate system using Amira and scripts written in Matlab for post-processing. Normalized newly mineralized and eroded bone volume (MV/BV, EV/BV), normalized formed and eroded bone surface area (MS/BS, ES/BS), mineralized thickness (MTh) and eroded depth (ED) were quantified. ANOVA was performed to examine the effect of loading and injection. Loading significantly increased the periosteal MV/BV, periosteal and endosteal MS/BS as well as decreased the periosteal EV/BV and periosteal and endocortical ES/BS. Endosteal MV/BV or EV/BV were not affected, which may be due to differences in the local strain environment at the two surfaces. In addition, mechanical stimuli did not influence ED, but led to diminished periosteal EV/BV and periosteal ES/BS suggesting fewer resorption sites in tibiae subjected to loading. Injection significantly affected periosteal and endosteal bone formation and resorption (Fig.1). Significant increases in cortical bone mass of loaded MM mice were accompanied by decreases in tumor load as evidenced by MOPC315.BM specific IgA levels (Fig. 2A). Interestingly, quantification of tibial and whole body bioluminescence signal intensities revealed controlled tumor growth in the loaded left tibia and a further delay of tumor cell dissemination throughout body of MM mice (Fig. 2B). Our data provide evidence that skeletal mechanical stimuli have anti-myeloma effects and rescue osteolytic bone loss in MMBD. The anabolic response to mechanical loads outweighs the anti-resorptive effect of MM cells, suggesting a combination of loading with bone resorption inhibitors in future therapeutic strategies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

1022 - Macrophages are Essential Regulators of Hematopoietic and Bone Tissues

Macrophages are dispersed throughout the bone marrow (BM) and present at the endosteum and periosteum. Macrophages are key regulators of the bone tissue and hematopoietic stem and progenitor cell (HSPC) niches. Therapeutic administration of G-CSF causes the collapse of HSPC niche function with reduced expression of HSPC-supportive niche factors resulting in HSPC mobilization into the blood together with an arrest in endosteal bone formation. We and others have shown that these effects are mediated in part by BM macrophages. Indeed G-CSF supresses several BM macrophage subsets and various methods to deplete macrophage subsets lead to similar collapse of HSPC niche function and HSPC mobilization. The HSPC niche-supporting role of macrophages is confirmed by the facts that G-CSF causes similar collapse of HSPC niches and HSPC mobilization in mice expressing its receptor solely in macrophages / monocytes but not in granulocytes. Reciprocally, we find that a subset of BM-resident CD169+ macrophages is essential for HSC engraftment following lethal irradiation. These host-derived BM macrophages are radio-resistant, divide autonomously following lethal irradiation and HSC transplant, are necessary for optimal HSC engraftment and cannot be replaced by donor HSC-derived macrophages / monocytes to ensure HSC engraftment. The bone is also critically dependent on macrophages. Both endosteum and periosteum are lined by a canopy of specialized macrophages above the layer of active osteoblasts. These “osteomacs” are necessary to maintain osteoblast differentiation and function. We have recently shown that similar to HSPC niche supportive macrophages, osteomacs express CD169, are depleted in response to G-CSF and required for bone repair following fractures. Finally we have recently shown that macrophages/ monocytes are essential to the pathological formation of ectopic bones and HSPC niches. Heterotopic ossification is a frequent pathology in patients suffering traumatic brain or spinal cord injury (SCI). They form in the periarticular muscles and can completely ankylose the affected joints. These debilitating “neurogenic” heterotopic ossifications (NHO) contain a functional hematopoietic BM with HSC capable of hematopoietic engraftment in transplanted mice. In a mouse model of SCI-Induced NHO that we have developed, we have found that macrophages/monocytes are key drivers of these NHO in part via oncostatin M secreted by macrophages. In conclusion macrophages are key regulators of haematopoiesis and bone tissue and key drivers of the pathological formation of ectopic bones and HSPC niches.

Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche.

Myeloma bone disease is a devastating complication of multiple myeloma (MM) and is caused by dysregulation of bone remodeling processes in the bone marrow microenvironment. Previous studies showed that microRNA-138 (miR-138) is a negative regulator of osteogenic differentiation of mesenchymal stromal cells (MSCs) and that inhibiting its function enhances bone formation in vitro. In this study, we explored the role of miR-138 in myeloma bone disease and evaluated the potential of systemically delivered locked nucleic acid (LNA)-modified anti-miR-138 oligonucleotides in suppressing myeloma bone disease. We showed that expression of miR-138 was significantly increased in MSCs from MM patients (MM-MSCs) and myeloma cells compared to those from healthy subjects. Furthermore, inhibition of miR-138 resulted in enhanced osteogenic differentiation of MM-MSCs in vitro and increased the number of endosteal osteoblastic lineage cells (OBCs) and bone formation rate in mouse models of myeloma bone disease. RNA sequencing of the OBCs identified TRPS1 and SULF2 as potential miR-138 targets that were de-repressed in anti-miR-138-treated mice. In summary, these data indicate that inhibition of miR-138 enhances bone formation in MM and that pharmacological inhibition of miR-138 could represent a new therapeutic strategy for treatment of myeloma bone disease.

Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.

Hyperostosis Cranialis Interna (HCI) is a rare bone disorder characterized by progressive intracranial bone overgrowth at the skull. Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14). We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc, resulting in hyper-activation of cAMP-CREB and NFAT signaling. Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients. Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone phenotype. The effects of osteoblastic overexpression of L438R Zip14 therefore mimic the disparate actions of estrogen on cortical and trabecular bone through osteoblasts. Collectively, we reveal ZIP14 as a novel regulator of bone homeostasis, and that manipulating ZIP14 might be a therapeutic strategy for bone diseases.

Cortical bone loss due to skeletal unloading in aldehyde dehydrogenase 2 gene knockout mice is associated with decreased PTH receptor expression in osteocytes

Aldehyde dehydrogenase 2 (ALDH2) is the enzyme that degrades and detoxifies the acetaldehyde produced by alcohol metabolism. In our previous study, we found that compared with wild-type mice (WT), climbing exercises did not increase trabecular bone mass in Aldh2 knockout mice (KO). The purpose of this study was to clarify the effect of the Aldh2 gene on cortical bone structure and on the dynamics of skeletal unloading. Eight-week-old male KO and WT were divided into ground control (GC) or tail suspension (TS) groups for one week (i.e., the KOGC, KOTS, WTGC and WTTS groups). We measured the bone mineral density (BMD) of the femur using dual-energy X-ray absorptiometry. We assessed the femoral morphometry using peripheral quantitative computed tomography (pQCT) and evaluated the femoral cortex histomorphometry, and cortical mRNA using quantitative RT-PCR and cortical bone immunohistostaining. No significant differences were found between the femoral BMD of WTGC and that of WTTS, but the BMD in KOTS was significantly lower than that of KOGC. The pQCT results revealed that the cortical BMD of the femoral diaphysis in KOTS was significantly lower than that of KOGC. Furthermore, the cortical bone area and cortical thickness were significantly lower in KOTS than in the other three groups. Cortical histomorphometric analysis revealed that the endosteal and periosteal bone formation parameters were significantly lower in KOTS than in KOGC. Bone formation signals such as parathyroid hormone receptor (PTHR) were significantly decreased in KOTS compared with the levels in KOGC. Cortical bone immunohistostaining revealed a significantly decreased expression of PTHR in the osteocytes of KOTS compared with the expression level in KOGC. Thus, we concluded that when the Aldh2 gene is disrupted, skeletal unloading suppresses bone formation to decrease cortical bone mass, which may be mediated by a decreased expression of PTH receptors in osteocytes.

Cementless Mallory Head HA-coated femoral prosthesis in primary total hip arthroplasty: Clinical and radiological results of a four to nine year prospective study.

We prospectively studied 152 hips in 126 patients with a proximally porous and hydroxyapatite coated double tapered straight femoral prosthesis. The follow-up period was 4.2 to 9.6 years. All but two prostheses showed osseo-integration. The mean Harris hip score (HHS) increased from 40 to 92 points and 97% of the patients had no or only mild pain. Limping and the use of walking aids decreased substantially after the operation. The morphology of positive bone remodelling with either endosteal bone formation or periosteal bone formation was correlated with the stem fit in the medullary canal (p=0.0001). Negative bone remodelling features could not be demonstrated. There was no correlation between the clinical parameters and the radiological phenomena. (Hip International 2002; 4: 345-56).

To assess the 2-year clinical and radiologic results with an entirely HA-coated total hip replacement, with an emphasis on periprosthetic bone remodelling

Total hip arthroplasty (THA) is one of the most successful surgical procedures that has been introduced and today over 1.5 million THA’s are performed annually in the world. The development of THA in the 60’s by Sir John Charnley represents a milestone in orthopaedic surgery. The most common indication for THA is primary osteoarthritis, a degenerative disorder of the cartilage and the surrounding tissues. However, 8-9% of the THA’s performed sooner or later need to be re-operated. Revision arthroplasty is a challenging procedure, costly and with a less reliable outcome. The main reason for failure leading to revision is aseptic loosening. Both mechanical and biological effects act in the loosening process, the dominating factor may be one or the other, depending on a number of circumstances, including implant design, fixation mode and technique, as well as biologic factors unique to the individual. Our purpose of this study is to determine the performance of, and periprosthetic bone response to hydroxyapatite (HA)–coated hip implant at least 2 years after insertion. This is both prospective & retrospective study of patients operated with uncemented fully HA coated THR in our institute, Sample size taken is 30 patients of institute who have undergone uncemented fully HA coated THR. We have taken Patients with un cemented fully HA coated THR done, At least 2 year back in hospital as a Inclusion criteria. In exclusion criteria we have excluded Patient with uncemented partially HA coated THR and Patients with anterior thigh pain before operation. Our procedure of study was Clinical follow up of patients pre-op, immediate post op, 12months & 24 months using anterior thigh pain. Radiological follow up through x-rays at pre-op, immediate post op, 12 months & 24 months. Anteroposterior radiographs of the pelvis and femurs cantered over the pubis, and lateral views of the femurs were standardized by using the same film quality, developing process, exposure, target distance, magnification, and field and keeping the leg in the same position. The linear measurements were made by a calliper and corrected for magnification of the radiographs, using the diameter of the head of the femoral component as reference. Femoral zonal analysis was performed on the anteroposterior radiographs as described by Gruen et al. and on the lateral radiographs according to Johnston et al. spot welds that is diaphyseal endosteal bone formation were noted in both anteroposterior and lateral x-rays. Subsidence of the stem was measured by the vertical distance from the lateral shoulder of the prosthesis to the superior tip of the greater trochanter or to the tip of the lesser trochanter. Varus or valgus migration was determined by measuring the angle made by the intersection of a line through the midstem of the prosthesis and a line through the midshaft of the femur as seen on the anteroposterior radiograph. End point of study was completion of clinical and radiological follow up of 30 patients. Results shown by this study reviews 38 hips in 30 patients who were followed up for a average of 32 months (range 24- 96 months). There were 22 male and 8 female patients. The average age was 41years (range, 14-55 years). The diagnosis was AVN in 28 hips, Ankylosing spondylitis in 7 hips, Fracture neck femur in 2 hips, Koch’s in 1 hip. 6 hips had undergone prior procedures, including osteosynthesis of femoral neck fracture. Clinically Result shows Hip function rose to a near-normal level during the first year, and this result was maintained throughout the study. At 2 years, only 1 patient complained of vague, uncharacteristic hip pain, unrelated to walking. No patient suffered from thigh pain.

Bone Marrow Findings Secondary to Antineoplastic Compounds: Hematopoietic, Bone, and Cytokine Cross Talk.

New medullary bone formation has been observed in rats administered a variety of antineoplastic compounds. Similar effects reported in rats administered granulocyte colony-stimulating factor (G-CSF) were attributed to exaggerated pharmacology of G-CSF as a cytokine and growth factor, resulting in stromal proliferation in addition to the intended hematopoietic effects. Similar phenomena of marrow stromal change are reported among other species in association with various growth factors. Case study summaries of test item-related histopathologic changes in bone marrow, reflecting trabecular and/or endosteal new bone formation, are presented. In each of these cases, it was concluded that the new medullary bone and stromal proliferation did not reflect a primary target-related toxicity; rather, the mesenchymal changes were attributed to nonspecific, secondary effects of cytokines elaborated in response to primary cytotoxic effects on hematopoietic cells with subsequent impact on circulating blood cells. The common features associated with marrow stromal changes in the case studies, as well as with a variety of pharmacologic compounds across several species described in the literature, are hematologic effects and/or changes in growth factor levels and cytokine expression.

Old age causes de novo intracortical bone remodeling and porosity in mice.

Decreased cortical thickness and increased cortical porosity are the key anatomic changes responsible for osteoporotic fractures in elderly women and men. The cellular basis of these changes is unbalanced endosteal and intracortical osteonal remodeling by the osteoclasts and osteoblasts that comprise the basic multicellular units (BMUs). Like humans, mice lose cortical bone with age, but unlike humans, this loss occurs in the face of sex steroid sufficiency. Mice are therefore an ideal model to dissect age-specific osteoporotic mechanisms. Nevertheless, lack of evidence for endosteal or intracortical remodeling in mice has raised questions about their translational relevance. We show herein that administration of the antiosteoclastogenic cytokine osteoprotegerin to Swiss Webster mice ablated not only osteoclasts, but also endosteal bone formation, demonstrating the occurrence of BMU-based endosteal remodeling. Femoral cortical thickness decreased in aged male and female C57BL/6J mice, as well as F1 hybrids of C57BL/6J and BALB/cBy mice. This decrease was greater in C57BL/6J mice, indicating a genetic influence. Moreover, endosteal remodeling became unbalanced because of increased osteoclast and decreased osteoblast numbers. The porosity of the femoral cortex increased with age but was much higher in females of both strains. Notably, the increased cortical porosity resulted from de novo intracortical remodeling by osteon-like structures. Age-dependent cortical bone loss was associated with increased osteocyte DNA damage, cellular senescence, the senescence-associated secretory phenotype, and increased levels of RANKL. The demonstration of unbalanced endosteal and intracortical remodeling in old mice validates the relevance of this animal model to involutional osteoporosis in humans.