Review

Authors: Jonathan W Lowery, Vicki Rosen

Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor-β family of ligands. BMPs exhibit widespread utility and pleiotropic, context-dependent effects, and the strength and duration of BMP pathway signaling is tightly regulated at numerous levels via mechanisms operating both inside and outside the cell. Defects in the BMP pathway or its regulation underlie multiple human diseases of different organ systems. Yet much remains to be discovered about the BMP pathway in its original context, i.e., the skeleton. In this review, we provide a comprehensive overview of the intricacies of the BMP pathway and its inhibitors in bone development, homeostasis, and disease. We frame the content of the review around major unanswered questions for which incomplete evidence is available. First, we consider the gene regulatory network downstream of BMP signaling in osteoblastogenesis. Next, we examine why some BMP ligands are more osteogenic than others and what factors limit BMP signaling during osteoblastogenesis. Then we consider whether specific BMP pathway components are required for normal skeletal development, and if the pathway exerts endogenous effects in the aging skeleton. Finally, we propose two major areas of need of future study by the field: greater resolution of the gene regulatory network downstream of BMP signaling in the skeleton, and an expanded repertoire of reagents to reliably and specifically inhibit individual BMP pathway components.

Topics: Animals; Bone Morphogenetic Proteins; Gene Expression Regulation; Humans; Osteogenesis; Signal Transduction; Skeleton

PubMed: 30156494
DOI: 10.1152/physrev.00028.2017

Review

Authors: Bryan Mendelson, Chin-Ho Wong

UNLABELLED

In principle, to achieve the most natural and harmonious rejuvenation of the face, all changes that result from the aging process should be corrected. Traditionally, soft tissue lifting and redraping have constituted the cornerstone of most facial rejuvenation procedures. Changes in the facial skeleton that occur with aging and their impact on facial appearance have not been well appreciated. Accordingly, failure to address changes in the skeletal foundation of the face may limit the potential benefit of any rejuvenation procedure. Correction of the skeletal framework is increasingly viewed as the new frontier in facial rejuvenation. It currently is clear that certain areas of the facial skeleton undergo resorption with aging. Areas with a strong predisposition to resorption include the midface skeleton, particularly the maxilla including the pyriform region of the nose, the superomedial and inferolateral aspects of the orbital rim, and the prejowl area of the mandible. These areas resorb in a specific and predictable manner with aging. The resultant deficiencies of the skeletal foundation contribute to the stigmata of the aging face. In patients with a congenitally weak skeletal structure, the skeleton may be the primary cause for the manifestations of premature aging. These areas should be specifically examined in patients undergoing facial rejuvenation and addressed to obtain superior aesthetic results.

LEVEL OF EVIDENCE IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Topics: Adult; Aging; Cheek; Facial Bones; Humans; Middle Aged; Nose; Orbit; Prostheses and Implants; Prosthesis Implantation; Plastic Surgery Procedures; Rejuvenation; Zygoma

PubMed: 22580543
DOI: 10.1007/s00266-012-9904-3

Review

Authors: Florent Elefteriou

It is from the discovery of leptin and the central nervous system as a regulator of bone remodeling that the presence of autonomic nerves within the skeleton transitioned from a mere histological observation to the mechanism whereby neurons of the central nervous system communicate with cells of the bone microenvironment and regulate bone homeostasis. This shift in paradigm sparked new preclinical and clinical investigations aimed at defining the contribution of sympathetic, parasympathetic, and sensory nerves to the process of bone development, bone mass accrual, bone remodeling, and cancer metastasis. The aim of this article is to review the data that led to the current understanding of the interactions between the autonomic and skeletal systems and to present a critical appraisal of the literature, bringing forth a schema that can put into physiological and clinical context the main genetic and pharmacological observations pointing to the existence of an autonomic control of skeletal homeostasis. The different types of nerves found in the skeleton, their functional interactions with bone cells, their impact on bone development, bone mass accrual and remodeling, and the possible clinical or pathophysiological relevance of these findings are discussed.

Topics: Adaptation, Physiological; Animals; Autonomic Nervous System; Bone Development; Bone Diseases; Bone Remodeling; Bone and Bones; Humans; Weight-Bearing

PubMed: 29717928
DOI: 10.1152/physrev.00014.2017

Authors: James A McNamara, Lorenzo Franchi

The cervical vertebral maturation (CVM) method is used to determine the craniofacial skeletal maturational stage of an individual at a specific time point during the growth process. This diagnostic approach uses data derived from the second (C2), third (C3), and fourth (C4) cervical vertebrae, as visualized in a two-dimensional lateral cephalogram. Six maturational stages of those three cervical vertebrae can be determined, based on the morphology of their bodies. The first step is to evaluate the inferior border of these vertebral bodies, determining whether they are flat or concave (ie, presence of a visible notch). The second step in the analysis is to evaluate the shape of C3 and C4. These vertebral bodies change in shape in a typical sequence, progressing from trapezoidal to rectangular horizontal, to square, and to rectangular vertical. Typically, cervical stages (CSs) 1 and CS 2 are considered prepubertal, CS 3 and CS 4 circumpubertal, and CS 5 and CS 6 postpubertal. Criticism has been rendered as to the reproducibility of the CVM method. Diminished reliability may be observed at least in part due to the lack of a definitive description of the staging procedure in the literature. Based on the now nearly 20 years of experience in staging cervical vertebrae, this article was prepared as a "user's guide" that describes the CVM stages in detail in attempt to help the reader use this approach in everyday clinical practice.

Topics: Age Determination by Skeleton; Cervical Vertebrae; Female; Humans; Male; Radiography

PubMed: 29337631
DOI: 10.2319/111517-787.1

Authors: Daniel Richard, Pushpanathan Muthuirulan, Mariel Young...

Underlying variation in height are regulatory changes to chondrocytes, cartilage cells comprising long-bone growth plates. Currently, we lack knowledge on epigenetic regulation and gene expression of chondrocytes sampled across the human skeleton, and therefore we cannot understand basic regulatory mechanisms controlling height biology. We first rectify this issue by generating extensive epigenetic and transcriptomic maps from chondrocytes sampled from different growth plates across developing human skeletons, discovering novel regulatory networks shaping human bone/joint development. Next, using these maps in tandem with height genome-wide association study (GWAS) signals, we disentangle the regulatory impacts that skeletal element-specific versus global-acting variants have on skeletal growth, revealing the prime importance of regulatory pleiotropy in controlling height variation. Finally, as height is highly heritable, and thus often the test case for complex-trait genetics, we leverage these datasets within a testable omnigenic model framework to discover novel chondrocyte developmental modules and peripheral-acting factors shaping height biology and skeletal growth.

Topics: Humans; Genomics; Skeleton; Body Height; Quantitative Trait, Heritable; Gene Regulatory Networks; Chondrocytes; Genetic Association Studies; Epigenomics; Bone Development; Transcriptome

PubMed: 39549696
DOI: 10.1016/j.cell.2024.10.040

Review

Authors: Blayne A Sarazin, Claire L Ihle, Philip Owens...

PURPOSE OF REVIEW

In this review, we provide an overview of what is currently known about the impacts of mechanical stimuli on metastatic tumor-induced bone disease (TIBD). Further, we focus on the role of the osteocyte, the skeleton's primary mechanosensory cell, which is central to the skeleton's mechanoresponse, sensing and integrating local mechanical stimuli, and then controlling the downstream remodeling balance as appropriate.

RECENT FINDINGS

Exercise and controlled mechanical loading have anabolic effects on bone tissue in models of bone metastasis. They also have anti-tumorigenic properties, in part due to offsetting the vicious cycle of osteolytic bone loss as well as regulating inflammatory signals. The impacts of metastatic cancer on the mechanosensory function of osteocytes remains unclear. Increased mechanical stimuli are a potential method for mitigating TIBD.

Topics: Animals; Biomechanical Phenomena; Biophysics; Bone Neoplasms; Bone Remodeling; Humans; Mice; Osteocytes; Stress, Mechanical

PubMed: 34729693
DOI: 10.1007/s11914-021-00704-9

Review

Authors: X Sherry Liu, Liyun Wang, Chantal M J de Bakker...

PURPOSE OF REVIEW

This review summarizes recently published data on the effects of pregnancy and lactation on bone structure, mechanical properties, and mechano-responsiveness in an effort to elucidate how the balance between the structural and metabolic functions of the skeleton is achieved during these physiological processes.

RECENT FINDINGS

While pregnancy and lactation induce significant changes in bone density and structure to provide calcium for fetal/infant growth, the maternal physiology also comprises several innate compensatory mechanisms that allow for the maintenance of skeletal mechanical integrity. Both clinical and animal studies suggest that pregnancy and lactation lead to adaptations in cortical bone structure to allow for rapid calcium release from the trabecular compartment while maintaining whole bone stiffness and strength. Moreover, extents of lactation-induced bone loss and weaning-induced recovery are highly dependent on a given bone's load-bearing function, resulting in better protection of the mechanical integrity at critical load-bearing sites. The recent discovery of lactation-induced osteocytic perilacunar/canalicular remodeling (PLR) indicates a new means for osteocytes to modulate mineral homeostasis and tissue-level mechanical properties of the maternal skeleton. Furthermore, lactation-induced PLR may also play an important role in maintaining the maternal skeleton's load-bearing capacity by altering osteocyte's microenvironment and modulating the transmission of anabolic mechanical signals to osteocytes. Both clinical and animal studies show that parity and lactation have no adverse, or a positive effect on bone strength later in life. The skeletal effects during pregnancy and lactation reflect an optimized balance between the mechanical and metabolic functions of the skeleton.

Topics: Adaptation, Physiological; Animals; Biomechanical Phenomena; Bone Density; Bone Remodeling; Bone and Bones; Calcium; Cancellous Bone; Cortical Bone; Female; Humans; Lactation; Osteocytes; Pregnancy; Weaning; Weight-Bearing

PubMed: 31755029
DOI: 10.1007/s11914-019-00555-5

Review

Authors: Jiajia Xu, Zhongmin Zhang, Junjie Zhao...

The skeleton is one of the largest organ systems in the body and is richly innervated by the network of nerves. Peripheral nerves in the skeleton include sensory and sympathetic nerves. Crosstalk between bones and nerves is a hot topic of current research, yet it is not well understood. In this review, we will explore the role of nerves in bone repair and remodeling, as well as summarize the molecular mechanisms by which neurotransmitters regulate osteogenic differentiation. Furthermore, we discuss the skeleton's role as an endocrine organ that regulates the innervation and function of nerves by secreting bone-derived factors. An understanding of the interactions between nerves and bone can help to prevent and treat bone diseases caused by abnormal innervation or nerve function, develop new strategies for clinical bone regeneration, and improve patient outcomes.

PubMed: 36111341
DOI: 10.3389/fcell.2022.976736

Review

Authors: Sara S Sánchez, Romel S Sánchez

The axial skeleton of the has undergone an evolutionary reduction of its bone elements. This structural plan is strongly preserved throughout the order and would have emerged as a highly specialized anatomical adaptation to its locomotor jumping pattern. The development programs that direct the vertebral morphogenesis of the anurans are poorly described and the molecular bases that have caused their pattern to differ from other tetrapods are completely unknown. In this work, we review the ontogeny of the spinal column of the anurans and explore the genetic mechanisms that could explain the morphological difference and the maintenance of the body plan during evolution. Here, we propose that the absence of caudal osseous elements, as a consequence of the inability of sclerotomes to form cartilaginous condensations in frogs, could be due to changes in both pattern and expression levels of , , and genes along the anteroposterior axis. The anteriorised expression of the genes together with the reduction in the expression levels of , and in the posterior somites could explain, at least partly, the loss of caudal vertebrae in the anurans during evolution.

Topics: Animals; Anura; Bone and Bones; Gene Expression Regulation, Developmental; Genes, Homeobox; Skeleton; Somites

PubMed: 32930370
DOI: 10.1387/ijdb.200230ss

Authors: Eucharist Kun, Emily M Javan, Olivia Smith...

The human skeletal form underlies bipedalism, but the genetic basis of skeletal proportions (SPs) is not well characterized. We applied deep-learning models to 31,221 x-rays from the UK Biobank to extract a comprehensive set of SPs, which were associated with 145 independent loci genome-wide. Structural equation modeling suggested that limb proportions exhibited strong genetic sharing but were independent of width and torso proportions. Polygenic score analysis identified specific associations between osteoarthritis and hip and knee SPs. In contrast to other traits, SP loci were enriched in human accelerated regions and in regulatory elements of genes that are differentially expressed between humans and great apes. Combined, our work identifies specific genetic variants that affect the skeletal form and ties a major evolutionary facet of human anatomical change to pathogenesis.

Topics: Humans; Genome-Wide Association Study; Multifactorial Inheritance; Phenotype; Polymorphism, Single Nucleotide; Genome, Human; Skeleton; Evolution, Molecular; Male; Female

PubMed: 37471560
DOI: 10.1126/science.adf8009