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NELL-1 is a secreted, osteoinductive protein whose expression rheostatically controls skeletal ossification. Overexpression of NELL-1 results in craniosynostosis in humans and mice, whereas lack of Nell-1 expression is associated with skeletal undermineralization. Here we show that Nell-1 -haploinsufficient mice have normal skeletal development but undergo age-related osteoporosis, characterized by a reduction in osteoblast:osteoclast (OB:OC) ratio and increased bone fragility. Recombinant NELL-1 binds to integrin β1 and consequently induces Wnt/β-catenin signalling, associated with increased OB differentiation and inhibition of OC-directed bone resorption. Systemic delivery of NELL-1 to mice with gonadectomy-induced osteoporosis results in improved bone mineral density. When extended to a large animal model, local delivery of NELL-1 to osteoporotic sheep spine leads to significant increase in bone formation. Altogether, these findings suggest that NELL-1 deficiency plays a role in osteoporosis and demonstrate the potential utility of NELL-1 as a combination anabolic/antiosteoclastic therapeutic for bone loss. The growth factor NELL-1 induces bone formation during development, but its role in osteoporosis is unknown. This study shows that NELL-1 binding to integrin ß1 induces Wnt/ß-catenin signalling in the bone and restores bone mineral density in osteoporotic mice and sheep, suggesting the therapeutic potential of NELL-1 for the treatment of bone loss.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-20933-x .

Although the skeleton's adaptability to load-bearing has been recognized for over a century, the specific mechanical components responsible for strengthening it have not been identified. Here we show that after mechanically stimulating the hindlimbs of adult sheep on a daily basis for a year with 20-minute bursts of very-low-magnitude, high-frequency vibration, the density of the spongy (trabecular) bone in the proximal femur is significantly increased (by 34.2%) compared to controls. As the strain levels generated by this treatment are three orders of magnitude below those that damage bone tissue, this anabolic, non-invasive stimulus may have potential for treating skeletal conditions such as osteoporosis.

Tissue cryo-sectioning combined with atomic force microscopy imaging reveals that the nanoscale morphology of dermal collagen fibrils, quantified using the metric of D-periodic spacing, changes under the condition of estrogen depletion. Specifically, a new subpopulation of fibrils with D-spacings in the region between 56 and 59nm is present 2 years following ovariectomy in ovine dermal samples. In addition, the overall width of the distribution, both values above and below the mean, was found to be increased. The change in width due to an increase in lower values of D-spacings was previously reported for ovine bone; however, this report demonstrates that the effect is also present in non-mineralized collagen fibrils. A nonparametric Kolmogorov–Smirnov test of the cumulative density function indicates a statistical difference in the sham and OVX D-spacing distributions (P<0.01).

Purpose The ovine model is often used to evaluate new spine fusion technologies prior to clinical testing. An important aspect of designing sheep surgery protocols is to select the appropriate postoperative time period for comparing fusion outcomes. Unfortunately, determining the ideal study endpoint is complicated by the fact that prior published studies have not used consistent timeframes. Thus, the primary aim of this study was to provide a reference for investigators as to the expected fusion outcomes of control groups at varying timepoints in sheep spine surgery models. Methods We identified published sheep fusion studies using autograft, interbody cages, and/or instrumentation. Fusion data were extracted, converted to a common scale, and analyzed across studied timepoints. Results Overall, 29 studies of 360 fusion levels were identified: 11 ALIF (158 levels), 3 PLIF/TLIF (28 levels), 8 PLF (90 levels), and 7 ACDF (84 levels). Studied timepoints ranged from 4 to 48 weeks postoperative. In general, fusion rates varied across techniques and instrumentation. The time to reach solid fusion differed by as many as 20 weeks between control groups. Conclusions Recommended timeframes for future studies designed to show either superiority over controls or equivalent outcomes with controls were developed based on aggregate results. Designating ideal study endpoints for sheep fusion models has both ethical implications associated with responsible use of animals in research, and economic implications given the cost of animal research. The current results can guide the development of future research methods and help investigators choose appropriate study timelines for various control groups.

Bone quantity, or density, has insufficient power to discriminate fracture risk in individuals. Additional measures of bone quality, such as microarchitectural characteristics and bone tissue properties, including the presence of damage, may improve the diagnosis of fracture risk. Microdamage and microarchitecture are two aspects of trabecular bone quality that are interdependent, with several microarchitectural changes strongly correlated to damage risk after compensating for bone density. This study aimed to delineate the effects of microarchitecture and estrogen depletion on microdamage susceptibility in trabecular bone using an ovariectomized sheep model to mimic post-menopausal osteoporosis. The propensity for microdamage formation in trabecular bone of the distal femur was studied using a sequence of compressive and torsional overloads. Ovariectomy had only minor effects on the microarchitecture at this anatomic site. Microdamage was correlated to bone volume fraction and structure model index (SMI), and ovariectomy increased the sensitivity to these parameters. The latter may be due to either increased resorption cavities acting as stress concentrations or to altered bone tissue properties. Pre-existing damage was also correlated to new damage formation. However, sequential loading primarily generated new cracks as opposed to propagating existing cracks, suggesting that pre-existing microdamage contributes to further damage of bone by shifting load bearing to previously undamaged trabeculae, which are subsequently damaged. The transition from plate-like to rod-like trabeculae, indicated by SMI, dictates this shift, and may be a hallmark of bone that is already predisposed to accruing greater levels of damage through compromised microarchitecture.

Bone morphogenetic proteins (BMPs) are widely used as bone graft substitutes in spinal fusion, but are associated with numerous adverse effects. The growth factor Nel-like molecule-1 (Nell-1) is mechanistically distinct from BMPs and can minimize complications associated with BMP therapies. This study evaluates the efficacy of Nell-1 combined with demineralized bone matrix (DBM) as a novel bone graft material for interbody spine fusion using sheep, a phylogenetically advanced animal with biomechanical similarities to human spine. Nell-1+sheep DBM or Nell-1+heat-inactivated DBM (inDBM) (to determine the osteogenic effect of residual growth factors in DBM) were implanted in surgical sites as follows: (1) DBM only (control) (n=8); (2) DBM+0.3 mg/mL Nell-1 (n=8); (3) DBM+0.6 mg/mL Nell-1 (n=8); (4) inDBM only (control) (n=4); (5) inDBM+0.3 mg/mL Nell-1 (n=4); (6) inDBM+0.6 mg/mL Nell-1 (n=4). Fusion was assessed by computed tomography, microcomputed tomography, and histology. One hundred percent fusion was achieved by 3 months in the DBM+0.6 mg/mL Nell-1 group and by 4 months in the inDBM+0.6 mg/mL Nell-1 group; bone volume and mineral density were increased by 58% and 47%, respectively. These fusion rates are comparable to published reports on BMP-2 or autograft bone efficacy in sheep. Nell-1 is an independently potent osteogenic molecule that is efficacious and easily applied when combined with DBM.

BackgroundMost rotator cuff surgery is performed on chronic tears. As there is no animal model in which to examine the physiology of muscle and tendon injury and repair in this setting, we developed a chronic rotator cuff injury model in sheep.MethodsThe infraspinatus tendon was released in thirty-six female sheep. Biopsy specimens were obtained from the muscle and were analyzed for fat content. The force generated by the muscle with supramaximal stimulation was recorded intraoperatively. A control group (twelve sheep) underwent an immediate tendon repair. In the remaining twenty-four sheep, the tendon was wrapped in a dura substitute to prevent scarring and was repaired at six weeks (eight sheep) and eighteen weeks (sixteen sheep) after release. In the immediate repair group, four animals were killed at six weeks; four, at twelve weeks; and four, at twenty weeks. In the six-week delayed repair group, four animals were killed at twelve weeks and four were killed at twenty weeks after the repair. In the eighteen-week delayed repair group, eight animals were killed at twelve weeks; four, at twenty weeks; and four, at thirty weeks after the repair. Muscle biopsies and testing were repeated prior to killing of the animals.ResultsThe average force of muscle contraction decreased 3.6 lb (1.6 kg) by six weeks after the injury and 3.9 lb (1.8 kg) by eighteen weeks after the injury. After the repair, the force of contraction in the six-week group improved by 0.8 lb (0.4 kg) at twelve weeks postoperatively and by 1.3 lb (0.6 kg) at twenty weeks postoperatively. In contrast, no improvement occurred in the eighteen-week group until thirty weeks after the repair, at which time a 0.9-lb (0.4-kg) improvement was noted. There was a twelvefold increase in intramuscular fat concentration; this lipid infiltration was partially reversed after the tendon repair. Isolated tendon samples demonstrated an increase in the modulus of elasticity after chronic detachment that partially corrected after the tendon repair in the earlier (six-week) repair group.ConclusionsWe found that earlier repair of the tendon results in a more rapid recovery of both muscle function and tendon elasticity compared with a more delayed repair. We concluded that there may be a “point of no return” in rotator cuff injury after which the elasticity of the muscle-tendon unit does not return to normal.Clinical RelevanceInjury and subsequent healing of the rotator cuff is a complex process that is poorly understood. We established a chronic rotator cuff injury and repair model in sheep. The model is reproducible and can be used to analyze both a direct repair of tendon to bone (chronic group) and an indirect repair requiring augmentation with a degradable patch (irreparable group).

A prospective, randomized study was performed in an ovine model to compare the efficacy of an anorganic bovine-derived hydroxyapatite matrix combined with a synthetic 15 amino acid residue (ABM/P-15) in facilitating lumbar interbody fusion when compared with autogenous bone harvested from the iliac crest. P-15 is a biomimetic to the cell-binding site of Type-I collagen for bone-forming cells. When combined with ABM, it creates the necessary scaffold to initiate cell invasion, binding, and subsequent osteogenesis. In this study, six adult ewes underwent anterior-lateral interbody fusion at L3/L4 and L4/L5 using PEEK interbody rings filled with autogenous bone at one level and ABM/P-15 at the other level and no additional instrumentation. Clinical CT scans were obtained at 3 and 6 months; micro-CT scans and histomorphometry analyses were performed after euthanization at 6 months. Clinical CT scan analysis showed that all autograft and ABM/P-15 treated levels had radiographically fused outside of the rings at the 3-month study time point. Although the clinical CT scans of the autograft treatment group showed significantly better fusion within the PEEK rings than ABM/P-15 at 3 months, micro-CT scans, clinical CT scans, and histomorphometric analyses showed there were no statistical differences between the two treatment groups at 6 months. Thus, ABM/P-15 was as successful as autogenous bone graft in producing lumbar spinal fusion in an ovine model, and it should be further evaluated in clinical studies.