The Interplay of Lipid Signaling in Musculoskeletal Cross Talk: Implications for Health and Disease.

The intricate interplay between the muscle and bone tissues is a fundamental aspect of musculoskeletal physiology. Over the past decades, emerging research has highlighted the pivotal role of lipid signaling in mediating communication between these tissues. This chapter delves into the multifaceted mechanisms through which lipids, particularly phospholipids, sphingolipids, and eicosanoids, participate in orchestrating cellular responses and metabolic pathways in both muscle and bone. Additionally, we examine the clinical implications of disrupted lipid signaling in musculoskeletal disorders, offering insights into potential therapeutic avenues. This chapter aims to shed light on the complex lipid-driven interactions between the muscle and bone tissues, paving the way for a deeper understanding of musculoskeletal health and disease.

Zebrafish as a Model for Lipidomics and Similar Investigations.

Zebrafish (Danio rerio) has emerged as a pivotal model organism in vertebrate development research over several decades. Beyond its contributions to developmental biology, zebrafish have increasingly played a crucial role in the field of lipidomics. Lipidomics, a comprehensive analysis of lipids within biological systems, offers profound insights into lipid metabolism and signaling pathways. This chapter explores the zebrafish's unique attributes that make it an ideal candidate for lipidomics studies. With a genome sharing numerous genetic similarities with humans, zebrafish serve as a powerful model for dissecting lipid metabolism and unraveling the complexities of lipid mediator-related diseases. In this chapter, we delve into specific protocols tailored for utilizing zebrafish in lipidomics research and similar investigations. Through a comprehensive exploration of zebrafish as a model organism, this chapter aims to provide researchers with valuable insights and methodologies for advancing lipidomics studies using zebrafish.

The paradox of bone mineral density and fracture risk in type 2 diabetes.

Fracture risk in type 2 diabetes (T2D) patients is paradoxically increased despite no decrease in areal bone mineraldensity (BMD). This phenomenon, known as the "diabetic bone paradox", has been attributed to various factorsincluding alterations in bone microarchitecture and composition, hyperinsulinemia and hyperglycemia, advancedglycation end products (AGEs), and comorbidities associated with T2D. Zhao et al. recently investigated therelationship between T2D and fracture risk using both genetic and phenotypic datasets. Their findings suggest thatgenetically predicted T2D is associated with higher BMD and lower fracture risk, indicating that the bone paradox isnot observed when confounding factors are controlled using Mendelian randomization (MR) analysis. However, inprospective phenotypic analysis, T2D remained associated with higher BMD and higher fracture risk, even afteradjusting for confounding factors. Stratified analysis revealed that the bone paradox may disappear when T2Drelatedrisk factors are eliminated. The study also highlighted the role of obesity in the relationship between T2Dand fracture risk, with BMI mediating a significant portion of the protective effect. Overall, managing T2D-relatedrisk factors may be crucial in preventing fracture risk in T2D patients.

Septin 7 interacts with Numb to preserve sarcomere structural organization and muscle contractile function.

Here, we investigated the mechanisms by which aging-related reductions of the levels of Numb in skeletal muscle fibers contribute to loss of muscle strength and power, two critical features of sarcopenia. Numb is an adaptor protein best known for its critical roles in development, including asymmetric cell division, cell-type specification, and termination of intracellular signaling. Numb expression is reduced in old humans and mice. We previously showed that, in mouse skeletal muscle fibers, Numb is localized to sarcomeres where it is concentrated near triads; conditional inactivation of Numb and a closely related protein Numb-like (Numbl) in mouse myofibers caused weakness, disorganization of sarcomeres, and smaller mitochondria with impaired function. Here, we found that a single knockout of Numb in myofibers causes reduction in tetanic force comparable to a double Numb, Numbl knockout. We found by proteomics analysis of protein complexes isolated from C2C12 myotubes by immunoprecipitation using antibodies against Numb that Septin 7 is a potential Numb-binding partner. Septin 7 is a member of the family of GTP-binding proteins that organize into filaments, sheets, and rings, and is considered part of the cytoskeleton. Immunofluorescence evaluation revealed a partial overlap of staining for Numb and Septin 7 in myofibers. Conditional, inducible knockouts of Numb led to disorganization of Septin 7 staining in myofibers. These findings indicate that Septin 7 is a Numb-binding partner and suggest that interactions between Numb and Septin 7 are critical for structural organization of the sarcomere and muscle contractile function.

Shared genetic architecture highlights the bidirectional association between major depressive disorder and fracture risk.

Background: There is limited evidence suggesting that osteoporosis might exacerbate depressive symptoms, while more studies demonstrate that depression negatively affects bone density and increases fracture risk. Aims: To explore the relationship between major depressive disorder (MDD) and fracture risk. Methods: We conducted a nested case-control analysis (32 670 patients with fracture and 397 017 individuals without fracture) and a matched cohort analysis (16 496 patients with MDD and 435 492 individuals without MDD) in the same prospective UK Biobank data set. Further, we investigated the shared genetic architecture between MDD and fracture with linkage disequilibrium score regression and the MiXeR statistical tools. We used the conditional/conjunctional false discovery rate approach to identify the specific shared loci. We calculated the weighted genetic risk score for individuals in the UK Biobank and logistic regression was used to confirm the association observed in the prospective study. Results: We found that MDD was associated with a 14% increase in fracture risk (hazard ratio (HR) 1.14, 95% CI 1.14 to 1.15, p<0.001) in the nested case-control analysis, while fracture was associated with a 72% increase in MDD risk (HR 1.72, 95% CI 1.64 to 1.79, p<0.001) in the matched cohort analysis, suggesting a longitudinal and bidirectional relationship. Further, genetic summary data suggested a genetic overlap between MDD and fracture. Specifically, we identified four shared genomic loci, with the top signal (rs7554101) near SGIP1. The protein encoded by SGIP1 is involved in cannabinoid receptor type 1 signalling. We found that genetically predicted MDD was associated with a higher risk of fracture and vice versa. In addition, we found that the higher expression level of SGIP1 in the spinal cord and muscle was associated with an increased risk of fracture and MDD. Conclusions: The genetic pleiotropy between MDD and fracture highlights the bidirectional association observed in the epidemiological analysis. The shared genetic components (such as SGIP1) between the diseases suggest that modulating the endocannabinoid system could be a potential therapeutic strategy for both MDD and bone loss.

Deciphering the complex relationship between type 2 diabetes and fracture risk with both genetic and observational evidence.

The 'diabetic bone paradox' suggested that type 2 diabetes (T2D) patients would have higher areal bone mineral density (BMD) but higher fracture risk than individuals without T2D. In this study, we found that the genetically predicted T2D was associated with higher BMD and lower risk of fracture in both weighted genetic risk score (wGRS) and two-sample Mendelian randomization (MR) analyses. We also identified ten genomic loci shared between T2D and fracture, with the top signal at SNP rs4580892 in the intron of gene RSPO3. And the higher expression in adipose subcutaneous and higher protein level in plasma of RSPO3 were associated with increased risk of T2D, but decreased risk of fracture. In the prospective study, T2D was observed to be associated with higher risk of fracture, but BMI mediated 30.2% of the protective effect. However, when stratified by the T2D-related risk factors for fracture, we observed that the effect of T2D on the risk of fracture decreased when the number of T2D-related risk factors decreased, and the association became non-significant if the T2D patients carried none of the risk factors. In conclusion, the genetically determined T2D might not be associated with higher risk of fracture. And the shared genetic architecture between T2D and fracture suggested a top signal around RSPO3 gene. The observed effect size of T2D on fracture risk decreased if the T2D-related risk factors could be eliminated. Therefore, it is important to manage the complications of T2D to prevent the risk of fracture.

A perspective on muscle phenotyping in musculoskeletal research.

Musculoskeletal research should synergistically investigate bone and muscle to inform approaches for maintaining mobility and to avoid bone fractures. The relationship between sarcopenia and osteoporosis, integrated in the term 'osteosarcopenia', is underscored by the close association shown between these two conditions in many studies, whereby one entity emerges as a predictor of the other. In a recent workshop of Working Group (WG) 2 of the EU Cooperation in Science and Technology (COST) Action 'Genomics of MusculoSkeletal traits Translational Network' (GEMSTONE) consortium (CA18139), muscle characterization was highlighted as being important, but currently under-recognized in the musculoskeletal field. Here, we summarize the opinions of the Consortium and research questions around translational and clinical musculoskeletal research, discussing muscle phenotyping in human experimental research and in two animal models: zebrafish and mouse.

Zebrafish as a Model for Osteoporosis: Functional Validations of Genome-Wide Association Studies.

PURPOSE OF REVIEW: GWAS, as a largely correlational analysis, requires in vitro or in vivo validation. Zebrafish (Danio rerio) have many advantages for studying the genetics of human diseases. Since gene editing in zebrafish has been highly valuable for studying embryonic skeletal developmental processes that are prenatally or perinatally lethal in mammalian models, we are reviewing pros and cons of this model. RECENT FINDINGS: The true power for the use of zebrafish is the ease by which the genome can be edited, especially using the CRISPR/Cas9 system. Gene editing, followed by phenotyping, for complex traits such as BMD, is beneficial, but the major physiological differences between the fish and mammals must be considered. Like mammals, zebrafish do have main bone cells; thus, both in vivo stem cell analyses and in vivo imaging are doable. Yet, the "long" bones of fish are peculiar, and their bone cavities do not contain bone marrow. Partial duplication of the zebrafish genome should be taken into account. Overall, small fish toolkit can provide unmatched opportunities for genetic modifications and morphological investigation as a follow-up to human-first discovery.

SEPTIN 7 INTERACTS WITH NUMB TO PRESERVE SARCOMERE STRUCTURAL ORGANIZATION AND MUSCLE CONTRACTILE FUNCTION.

Here, we investigated mechanisms by which aging-related reductions of the levels of Numb in skeletal muscle fibers contribute to loss of muscle strength and power, two critical features of sarcopenia. Numb is an adaptor protein best known for its critical roles in development including asymmetric cell division, cell-type specification and termination of intracellular signaling. Numb expression is reduced in old humans and mice. We previously showed that, in mouse skeletal muscle fibers, Numb is localized to sarcomeres where it is concentrated near triads; conditional inactivation of Numb and a closely related protein Numb-like (NumbL) in mouse myofibers caused weakness, disorganization of sarcomeres and smaller mitochondria with impaired function. Here, we found that a single knockout of Numb in myofibers causes reduction in tetanic force comparable to a double Numb, NumbL knockout. We found by proteomics analysis of protein complexes isolated from C2C12 myotubes by immunoprecipitation using antibodies against Numb, that Septin 7 is a potential Numb binding partner. Septin 7 is a member of the family of GTP-binding proteins that organize into filaments, sheets and rings, and is considered part of the cytoskeleton. Immunofluorescence evaluation revealed a partial overlap of staining for Numb and Septin 7 in myofibers. Conditional, inducible knockouts of Numb led to disorganization of Septin 7 staining in myofibers. These findings indicate that Septin 7 is a Numb binding partner and suggest that interactions between Numb and Septin 7 are critical for structural organization of the sarcomere and muscle contractile function.

Proceedings of the Post-Genome Analysis for Musculoskeletal Biology Workshop.

PURPOSE OF THE REVIEW: Herein, we report on the proceedings of the workshop entitled "Post-Genome analysis for musculoskeletal biology" that was held in July of 2022 in Safed, Galilee, Israel. Supported by the Israel Science Foundation, the goal of this workshop was to bring together established investigators and their trainees who were interested in understanding the etiology of musculoskeletal disease, from Israel and from around the world. RECENT FINDINGS: Presentations at this workshop spanned the spectrum from basic science to clinical studies. A major emphasis of the discussion centered on genetic studies in humans, and the limitations and advantages of such studies. The power of coupling studies using human data with functional follow-up studies in pre-clinical models such as mice, rats, and zebrafish was discussed in depth. The advantages and limitations of mice and zebrafish for faithfully modelling aspects of human disease were debated, specifically in the context of age-related diseases such as osteoporosis, osteoarthritis, adult-onset auto-immune disease, and osteosarcopenia. There remain significant gaps in our understanding of the nature and etiology of human musculoskeletal disease. While therapies and medications exist, much work is still needed to find safe and effective interventions for all patients suffering from diseases associated with age-related deterioration of musculoskeletal tissues. The potential of forward and reverse genetic studies has not been exhausted for diseases of muscles, joints, and bones.

Beneficial Effect of Vitamin D on Non-Alcoholic Fatty Liver Disease (NAFLD) Progression in the Zebrafish Model.

A major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) results from excessive liver fat accumulation. Vitamin D (VitD) plays multiple important roles in diverse physiologic processes. Here, we describe the role of VitD in the complex pathogenesis of NAFLD and explore the possible therapeutic role of VitD supplementation in NAFLD therapy. To compare the effect of VitD to other interventions such as low-calorie diet, we induced NAFLD in young adult zebrafish (Danio rerio, AB strain) and monitored the effects of VitD supplementation on the disease course. The zebrafish administered with high-dose VitD (1.25 µg) had significantly reduced liver fat compared to those that received low-dose VitD (0.049 µg) or caloric restriction. Gene expression analysis revealed that VitD downregulated several pathways that may play a role in NAFLD etiology, which affected fatty acid metabolism, vitamins and their cofactors, ethanol oxidation, and glycolysis. The pathway analysis revealed that the cholesterol biosynthesis pathway and the isoprenoid biosynthetic process pathway were significantly upregulated whereas the small molecule catabolic process pathway significantly downregulated following the exposure of NAFLD zebrafish model to high VitD dose. Therefore, our findings suggest the association of novel biochemical pathways with NAFLD and highlight the potential of VitD supplementation to reverse the severity of NAFLD, especially in younger people.

A variability in response of osteoclasts to zoledronic acid is mediated by smoking-associated modification in the DNA methylome.

BACKGROUND: Clinical trials have shown zoledronic acid as a potent bisphosphonate in preventing bone loss, but with varying potency between patients. Human osteoclasts ex vivo reportedly displayed a variable sensitivity to zoledronic acid > 200-fold, determined by the half-maximal inhibitory concentration (IC50), with cigarette smoking as one of the reported contributors to this variation. To reveal the molecular basis of the smoking-mediated variation on treatment sensitivity, we performed a DNA methylome profiling on whole blood cells from 34 healthy female blood donors. Multiple regression models were fitted to associate DNA methylation with ex vivo determined IC50 values, smoking, and their interaction adjusting for age and cell compositions. RESULTS: We identified 59 CpGs displaying genome-wide significance (p < 1e-08) with a false discovery rate (FDR) < 0.05 for the smoking-dependent association with IC50. Among them, 3 CpGs have p < 1e-08 and FDR < 2e-03. By comparing with genome-wide association studies, 15 significant CpGs were locally enriched (within < 50,000 bp) by SNPs associated with bone and body size measures. Furthermore, through a replication analysis using data from a published multi-omics association study on bone mineral density (BMD), we could validate that 29 out of the 59 CpGs were in close vicinity of genomic sites significantly associated with BMD. Gene Ontology (GO) analysis on genes linked to the 59 CpGs displaying smoking-dependent association with IC50, detected 18 significant GO terms including cation:cation antiporter activity, extracellular matrix conferring tensile strength, ligand-gated ion channel activity, etc. CONCLUSIONS: Our results suggest that smoking mediates individual sensitivity to zoledronic acid treatment through epigenetic regulation. Our novel findings could have important clinical implications since DNA methylation analysis may enable personalized zoledronic acid treatment.

Convergent genomics of longevity in rockfishes highlights the genetics of human life span variation.

Longevity is a defining, heritable trait that varies dramatically between species. To resolve the genetic regulation of this trait, we have mined genomic variation in rockfishes, which range in longevity from 11 to over 205 years. Multiple shifts in rockfish longevity have occurred independently and in a short evolutionary time frame, thus empowering convergence analyses. Our analyses reveal a common network of genes under convergent evolution, encompassing established aging regulators such as insulin signaling, yet also identify flavonoid (aryl-hydrocarbon) metabolism as a pathway modulating longevity. The selective pressures on these pathways indicate the ancestral state of rockfishes was long lived and that the changes in short-lived lineages are adaptive. These pathways were also used to explore genome-wide association studies of human longevity, identifying the aryl-hydrocarbon metabolism pathway to be significantly associated with human survival to the 99th percentile. This evolutionary intersection defines and cross-validates a previously unappreciated genetic architecture that associates with the evolution of longevity across vertebrates.

wnt16 regulates spine and muscle morphogenesis through parallel signals from notochord and dermomyotome.

Bone and muscle are coupled through developmental, mechanical, paracrine, and autocrine signals. Genetic variants at the CPED1-WNT16 locus are dually associated with bone- and muscle-related traits. While Wnt16 is necessary for bone mass and strength, this fails to explain pleiotropy at this locus. Here, we show wnt16 is required for spine and muscle morphogenesis in zebrafish. In embryos, wnt16 is expressed in dermomyotome and developing notochord, and contributes to larval myotome morphology and notochord elongation. Later, wnt16 is expressed at the ventral midline of the notochord sheath, and contributes to spine mineralization and osteoblast recruitment. Morphological changes in wnt16 mutant larvae are mirrored in adults, indicating that wnt16 impacts bone and muscle morphology throughout the lifespan. Finally, we show that wnt16 is a gene of major effect on lean mass at the CPED1-WNT16 locus. Our findings indicate that Wnt16 is secreted in structures adjacent to developing bone (notochord) and muscle (dermomyotome) where it affects the morphogenesis of each tissue, thereby rendering wnt16 expression into dual effects on bone and muscle morphology. This work expands our understanding of wnt16 in musculoskeletal development and supports the potential for variants to act through WNT16 to influence bone and muscle via parallel morphogenetic processes.

Both indirect maternal and direct fetal genetic effects reflect the observational relationship between higher birth weight and lower adult bone mass.

BACKGROUND: Birth weight is considered not only to undermine future growth, but also to induce lifelong diseases; the aim of this study is to explore the relationship between birth weight and adult bone mass. METHODS: We performed multivariable regression analyses to assess the association of birth weight with bone parameters measured by dual-energy X-ray absorptiometry (DXA) and by quantitative ultrasound (QUS), independently. We also implemented a systemic Mendelian randomization (MR) analysis to explore the causal association between them with both fetal-specific and maternal-specific instrumental variables. RESULTS: In the observational analyses, we found that higher birth weight could increase the adult bone area (lumbar spine, ß-coefficient= 0.17, P < 2.00 × 10-16; lateral spine, ß-coefficient = 0.02, P = 0.04), decrease bone mineral content-adjusted bone area (BMCadjArea) (lumbar spine, ß-coefficient= - 0.01, P = 2.27 × 10-14; lateral spine, ß-coefficient = - 0.05, P = 0.001), and decrease adult bone mineral density (BMD) (lumbar spine, ß-coefficient = - 0.04, P = 0.007; lateral spine; ß-coefficient = - 0.03, P = 0.02; heel, ß-coefficient = - 0.06, P < 2.00 × 10-16), and we observed that the effect of birth weight on bone size was larger than that on BMC. In MR analyses, the higher fetal-specific genetically determined birth weight was identified to be associated with higher bone area (lumbar spine; ß-coefficient = 0.15, P = 1.26 × 10-6, total hip, ß-coefficient = 0.15, P = 0.005; intertrochanteric area, ß-coefficient = 0.13, P = 0.0009; trochanter area, ß-coefficient = 0.11, P = 0.03) but lower BMD (lumbar spine, ß-coefficient = - 0.10, P = 0.01; lateral spine, ß-coefficient = - 0.12, P = 0.0003, and heel ß-coefficient = - 0.11, P = 3.33 × 10-13). In addition, we found that the higher maternal-specific genetically determined offspring birth weight was associated with lower offspring adult heel BMD (ß-coefficient = - 0.001, P = 0.04). CONCLUSIONS: The observational analyses suggested that higher birth weight was associated with the increased adult bone area but decreased BMD. By leveraging the genetic instrumental variables with maternal- and fetal-specific effects on birth weight, the observed relationship could be reflected by both the direct fetal and indirect maternal genetic effects.

Zebrafish mutants reveal unexpected role of Lrp5 in osteoclast regulation.

Low-density Lipoprotein Receptor-related Protein 5 (LRP5) functions as a co-receptor for Wnt ligands, controlling expression of genes involved in osteogenesis. In humans, loss-of-function mutations in LRP5 cause Osteoporosis-Pseudoglioma syndrome, a low bone mass disorder, while gain-of-function missense mutations have been observed in individuals with high bone mass. Zebrafish (Danio rerio) is a popular model for human disease research, as genetic determinants that control bone formation are generally conserved between zebrafish and mammals. We generated lrp5- knock-out zebrafish to study its role in skeletogenesis and homeostasis. Loss of lrp5 in zebrafish leads to craniofacial deformities and low bone mineral density (total body and head) at adult ages. To understand the mechanism and consequences of the observed phenotypes, we performed transcriptome analysis of the cranium of adult lrp5 mutants and siblings. Enrichment analysis revealed upregulation of genes significantly associated with hydrolase activity: mmp9, mmp13a, acp5a. acp5a encodes Tartrate-resistant acid phosphatase (TRAP) which is commonly used as an osteoclast marker, while Matrix metalloprotease 9, Mmp9, is known to be secreted by osteoclasts and stimulate bone resorption. These genes point to changes in osteoclast differentiation regulated by lrp5. To analyze these changes functionally, we assessed osteoclast dynamics in mutants and observed increased TRAP staining, significantly larger resorption areas, and developmental skeletal dysmorphologies in the mutant, suggesting higher resorptive activity in the absence of Lrp5 signaling. Our findings support a conserved role of Lrp5 in maintaining bone mineral density and revealed unexpected insights into the function of Lrp5 in bone homeostasis through moderation of osteoclast function.

General and abdominal obesity operate differently as influencing factors of fracture risk in old adults.

To infer the causality between obesity and fracture and the difference between general and abdominal obesity, a prospective study was performed in 456,921 participants, and 10,142 participants developed an incident fracture with follow-up period of 7.96 years. A U-shape relationship was observed between BMI and fracture, with the lowest risk of fracture in overweight participants. The obesity individuals had higher fracture risk when BMD was adjusted, and the protective effect of moderate-high BMI on fracture was mostly mediated by bone mineral density (BMD). However, for abdominal obesity, the higher WCadjBMI (linear) and HCadjBMI (J-shape) were found to be related to higher fracture risk, and less than 30% of the effect was mediated by BMD. By leveraging genetic instrumental variables, it provided additional evidences to support the aforementioned findings. In conclusion, keeping moderate-high BMI might be of benefit to old people in terms of fracture risk, whereas abdominal adiposity might increase risk of fracture.

NGLY1 Deficiency Zebrafish Model Manifests Abnormalities of the Nervous and Musculoskeletal Systems.

Background: NGLY1 is an enigmatic enzyme with multiple functions across a wide range of species. In humans, pathogenic genetic variants in NGLY1 are linked to a variable phenotype of global neurological dysfunction, abnormal tear production, and liver disease presenting the rare autosomal recessive disorder N-glycanase deficiency. We have ascertained four NGLY1 deficiency patients who were found to carry a homozygous nonsense variant (c.1294G > T, p.Glu432*) in NGLY1. Methods: We created an ngly1 deficiency zebrafish model and studied the nervous and musculoskeletal (MSK) systems to further characterize the phenotypes and pathophysiology of the disease. Results: Nervous system morphology analysis has shown significant loss of axon fibers in the peripheral nervous system. In addition, we found muscle structure abnormality of the mutant fish. Locomotion behavior analysis has shown hypersensitivity of the larval ngly1 (-/-) fish during stress conditions. Conclusion: This first reported NGLY1 deficiency zebrafish model might add to our understanding of NGLY1 role in the development of the nervous and MSK systems. Moreover, it might elucidate the natural history of the disease and be used as a platform for the development of novel therapies.

Functional Validation of Osteoporosis Genetic Findings Using Small Fish Models.

The advancement of human genomics has revolutionized our understanding of the genetic architecture of many skeletal diseases, including osteoporosis. However, interpreting results from human association studies remains a challenge, since index variants often reside in non-coding regions of the genome and do not possess an obvious regulatory function. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary, such as the one offered by animal models. These models enable us to identify causal mechanisms, clarify the underlying biology, and apply interventions. Over the past several decades, small teleost fishes, mostly zebrafish and medaka, have emerged as powerful systems for modeling the genetics of human diseases. Due to their amenability to genetic intervention and the highly conserved genetic and physiological features, fish have become indispensable for skeletal genomic studies. The goal of this review is to summarize the evidence supporting the utility of Zebrafish (Danio rerio) for accelerating our understanding of human skeletal genomics and outlining the remaining gaps in knowledge. We provide an overview of zebrafish skeletal morphophysiology and gene homology, shedding light on the advantages of human skeletal genomic exploration and validation. Knowledge of the biology underlying osteoporosis through animal models will lead to the translation into new, better and more effective therapeutic approaches.