Comparative data on the differentiation and growth of bone ornamentation in gnathostomes (Chordata: Vertebrata)

Bone ornamentation, in the form of rounded pits framed by a network of ridges, is a frequent feature among a great diversity of gnathostome taxa. However, the basic osteogenic processes controlling the differentiation and development of these reliefs remain controversial. The present study is a broad comparative survey of this question with the classical methods used in hard tissue histology and paleohistology. Distinct processes, unevenly distributed among taxa, are involved in the creation and growth of pits and ridges. The simplest one is mere differential growth between pit bottom (slow growth) and ridge top (faster growth). The involvement of several complex remodeling processes, with the local succession of resorption and reconstruction cycles, is frequent and occurs in all major gnathostome clades. Some broad, inclusive clades (e.g., Temnospondyli) display consistency in the mechanisms controlling ornamentation, whereas other clades (e.g., Actinopterygii) are characterized by the diversity of the mechanisms involved. If osteogenic mechanisms are taken into account, bone ornamentation should be considered as a character extremely prone to homoplasy. Maximum likelihood (ML) optimizations reveal that the plesiomorphic mechanism creating ornamentation is differential apposition rate over pits (slow growth) and ridges (faster growth). In some taxas e.g., temnospondyls vs lissamphibians or pseudosuchians, bone ornamentation is likely to be a homoplastic feature due to a convergence process driven by similar selective pressures. ML models of character evolution suggest that the presence of resorption in the development of ornamentation may be selectively advantageous, although support for this conclusion is only moderate. J. Morphol. 277:634–670, 2016. © 2016 Wiley Periodicals, Inc.     

Differentiation and growth of bone ornamentation in vertebrates: A comparative histological study among the Crocodylomorpha

Bone ornamentation, that is, hollow (pits and grooves) or protruding (ridges) repetitive reliefs on the surface of dermal bones, is a frequent, though poorly studied and understood, feature in vertebrates. One of the most typical examples of this characteristic is given by the Crurotarsi, a taxon formed by the crocodilians and their closest allies, which generally display deep ornamentation on skull roof and osteoderms. However, the ontogenetic process responsible for the differentiation and development of this character remains controversial. This study was conducted to settle the question on histological and microanatomical evidence in several crurotarsan taxa. Observational and experimental data in extant and extinct crocodyliforms show that bone ornamentation is initially created, and later maintained during somatic growth (that is indefinite in crocodilians), by a complex process of bone remodeling comprising local resorption of superficial bone cortices, followed by partial reconstruction. The superficial reliefs of crocodilian dermal bones are thus permanently modified through pit enlargement, drift, stretching, shrinking, or complete filling. Ridges are also remodeled in corresponding ways. These processes allow accommodation of unitary ornamental motifs to the overall dimensions of the bones during growth. A parsimony optimization based on the results of this study, but integrating also published data on bone histology in non‐crocodyliform crurotarsans and some non‐crurotarsan taxa, suggests that the peculiar mechanism described above for creating and maintaining bone ornamentation is a general feature of the Crurotarsi and is quite distinct from that attributed by previous authors to other vertebrates. J. Morphol. 276:425–445, 2015. © 2014 Wiley Periodicals, Inc.     

Growth requires bone resorption at particular skeletal elements in a teleost fish with acellular bone (Oreochromis niloticus, Teleostei: Cichlidae)

To date, little is known about bone resorption during skeletal development in teleostean fish with acellular bone. We report here about bone resorption with regard to growth in the tilapia Oreochromis niloticus. Nine skeletal elements obtained from growing juveniles were examined using histological and histochemical methods, and transmission electron microscopy (TEM). Tartrate-resistant acid phosphatase (TRAP) served as a marker for bone resorbing cells (osteoclasts), alkaline phosphatase (ALP) was used to identify osteoblasts, and alizarin staining indicated sites of bone formation. TRAP-activity was located at those skeletal elements where growth requires bone resorption, and at sites of cartilage degeneration. No TRAP-activity was found at those skeletal elements where resorption was not required for growth. The examination of the praeopercular shaft leads to a model of bone enlargement, including bone resorption by TRAP-positive cells located at the endosteal bone surface and bone formation by ALP-positive cells located at the periosteal bone surface. TRAP-positive cells were mononucleated and lacked a ruffled border. They appeared either as cell aggregates (resembling the shape of multinucleated giant cells) or as flat cells (resembling bone lining cells). Problems of osteoclast identification in bony fish are discussed.     

Alterations in skeletal and mineral metabolism following thermal injuries

Severe burns and other chronic inflammatory diseases are associated with altered skeletal metabolism that result in an increased incidence of osteopenia. In thermally injured children and adults there is a dramatic decrease in bone formation accompanied with an increase or maintenance of bone resorption. Children also exhibit a growth delay and subsequently fail to reach a predicted stature. Animal models, including the thermal injury mouse model, are being used to understand the mechanisms behind the uncoupling of bone formation and resorption that occurs following a major burn. The model has numerous commonalities with the human condition such as reduced bone formation, increased bone resorption, and decreased endochondral growth. The mechanisms that modulate calcium and skeletal metabolism following a thermal injury are complex and likely involve a number of endocrine, cytokine, and immune factors. Specifically, the potential roles of glucocorticoids, growth hormone, insulin-like growth factor-1, parathyroid hormone, interleukin-1 and -6, and tumor necrosis factor alpha are addressed. Subsequent to the increased survival rate of burn victims, there has been a heightened focus on therapeutic interventions that prevent or decrease the impact of thermal injuries on the skeletal system. These include exercise programs, exogenous recombinant human growth hormone, insulin, and oxandrolone.     

Evaluation of osteoclastic resorption activity using calcium phosphate coating combined with labeled polyanion

Osteoclasts are involved in bone resorption, and its activation is considered one of the causes of osteoporosis. The pit assay is the principal method for evaluating osteoclast function by measuring hydroxyapatite resorption in vitro. However, the pit assay requires time and trained techniques, including the pit image analysis, and there is no other easy method for evaluating bone resorption. In this study, we developed a novel approach to quantify the bone resorption activity using a calcium phosphate (CaP) coating labeled with fluorescent polyanion. Fluoresceinamine-labeled chondroitin polysulfate or Hoechst 33258-labeled deoxyribonucleic acid was used for CaP labeling. When macrophage cell line RAW264 was cultured on the labeled CaP under the stimulation with the receptor activator of the NF-κB ligand (RANKL), RAW264 cells differentiated into osteoclastic cells and the fluorescence intensity of the culture supernatant and pit area increased in a time- and dose-dependent manner. Furthermore, drugs for osteoporosis treatment, such as pamidronate and β-estradiol, inhibited fluorescein release by the cells stimulated with RANKL. A positive correlation between the fluorescence intensity and pit area was observed (r = 0.917). These results indicated that this new method using fluorescent polyanion-labeled CaP is a standardized useful assay system for the evaluation of bone resorption activity.     

Skeletal tissue and transforming growth factor beta

Normal skeletal growth results from a balance between the processes of bone matrix synthesis and resorption. These activities are regulated by both systemic and local factors. Bone turnover is dynamic, and skeletal growth must be maintained throughout life. Although many growth promoters are associated with bone matrix, it is enriched particularly with transforming growth factor beta (TGF-beta) activity. Experimental evidence indicates that TGF-beta regulates replication and differentiation of mesenchymal precursor cells, chondrocytes, osteoblasts, and osteoclasts. Recent studies further suggest that TGF-beta activity in skeletal tissue may be controlled at multiple levels by other local and systemic agents. Consequently, the intricate mechanisms by which TGF-beta regulates bone formation are likely to be fundamental to understanding the processes of skeletal growth during development, maintenance of bone mass in adult life, and healing subsequent to bone fracture.     

Inhibition of Sca-1-positive skeletal stem cell recruitment by alendronate blunts the anabolic effects of parathyroid hormone on bone remodeling

The anabolic effects of parathyroid hormone (PTH) on bone formation are impaired by concurrent use of antiresorptive drugs. We found that the release of active transforming growth factor (TGF)-β1 during osteoclastic bone resorption is inhibited by alendronate. We showed that mouse Sca-1-positive (Sca-1(+)) bone marrow stromal cells are a skeletal stem cell subset, which are recruited to bone remodeling sites by active TGF-β1 in response to bone resorption. Alendronate inhibits the release of active TGF-β1 and the recruitment of Sca-1(+) skeletal stem cells for the bone formation. The observation was validated in a Tgfb1(-/-) mouse model, in which the anabolic effects of PTH on bone formation are diminished. The PTH-stimulated recruitment of injected mouse Sca-1(+) cells to the resorptive sites was inhibited by alendronate. Thus, inhibition of active TGF-β1 release by alendronate reduces the recruitment of Sca-1(+) skeletal stem cells and impairs the anabolic action of PTH in bone.     

Morphometrics of compact bone: an example from Sudanese Nubia.

Morphometric analysis of compact femoral tissue was applied to a prehistoric population from Sudanese Nubia. Microradiographs of thin sections from below the lesser trochanter were examined. A total of 74 adults (40 females, 34 males) from the X-Group population (A.D. 350–550) were used to determine the underlying processes of bone remodeling in skeletal growth and maintenance. The relationship of bone turnover to the age of onset, patterning and frequency of cortical bone loss (osteoporosis) as a function of age and sex was examined. The cortical thickness, cortical area and formation/resorption frequencies were determined. Males exhibit a 4.9% net loss in cortical area, while females show a 10.7% loss. A substantial amount of female loss occurs in the third decade, with a slight gain in the fourth and a steady loss up to the sixth decade. These trends were further explored and refined histologically. The periosteal and endosteal frequencies for males show a variable but definite decrease in mineralization (i.e., increased numbers of osteons in the forming stage) and a slight increase in resorption. Third decade females show a marked difference with high frequencies of resorption spaces and forming osteons. It is suggested that in this population, stress related to childbearing and childrearing may be effecting the frequencies of formation foci and resorption spaces.     

Angiostatin inhibits bone metastasis formation in nude mice through a direct anti-osteoclastic activity

Bone is a very common metastatic site for breast cancer. In bone metastasis, there is a vicious circle wherein bone-residing metastatic cells stimulate osteoclast-mediated bone resorption, and bone-derived growth factors released from resorbed bone promote tumor growth. The contribution of tumor angiogenesis in the growth of bone metastases is, however, unknown. By using an experimental model of bone metastasis caused by MDA-MB-231/B02 breast cancer cells that quite closely mimics the conditions likely to occur in naturally arising metastatic human breast cancers, we demonstrate here that when MDA-MB-231/B02 cells were engineered to produce at the bone metastatic site an angiogenesis inhibitor, angiostatin, there was a marked inhibition in the extent of skeletal lesions. Inhibition of skeletal lesions came with a pronounced reduction in tumor burden in bone. However, although angiostatin produced by MDA-MB-231/B02 cells was effective at inhibiting in vitro endothelial cell proliferation and in vivo angiogenesis in a Matrigel implant model, we have shown that it inhibited cancer-induced bone destruction through a direct inhibition of osteoclast activity and generation. Overall, these results indicate that, besides its well known anti-angiogenic activity, angiostatin must also be considered as a very effective inhibitor of bone resorption, broadening its potential clinical use in cancer therapy.     

Bone resorption and bone remodelling in juvenile carp, Cyprinus carpio L.

The present study considers the important role of bone resorption for bone growth in general, and aims to clarify if and how bone resorption contributes to the skeletal development of carp, Cyprinus carpio L., a teleost species with ‘normal’ osteocyte‐containing (cellular) bone. To ensure the identification of osteoclasts and sites of bone resorption independently from the morphology of the bony cells, bones were studied by histological procedures, and by demonstration of the enzymes which serve as osteoclast markers, viz. tartrate resistant acid phosphatase (TRAP), ATPase and a vacuolar proton pump. Two types of bone‐resorbing cells were observed in juvenile carp: (1) multinucleated giant cells displaying morphological and biochemical attributes which are known from mammalian osteoclasts; and (b) flat cells which lack a visible ruffled border and for which identification requires the performance of enzyme histochemical procedures. Bone resorption performed by osteoclasts mainly occurs at endosteal bone surfaces. To a lesser extent, bone resorption also takes place at periosteal bone surfaces, but without an apparent connection to bone growth. The latter observation, and the occurrence of bone remodelling, suggest that the endoskeleton of juvenile carp might be involved in mineral metabolism. Morphological differences and biochemical similarities to bone resorption in teleosts with acellular bone are discussed.     

MMP-9 antisense oligodeoxynucleotide exerts an inhibitory effect on osteoclastic bone resorption by suppressing cell migration

We have previously shown that matrix metalloproteinases (MMPs) play a role in osteoclastic bone resorption by facilitating migration of osteoclastic cells toward bone surface through matrices. Of MMPs identified so far, MMP-9 is likely the most important proteinase for the action, since osteoclasts express this enzyme at a tremendously high level. However, no direct evidence has been provided to demonstrate its contribution to bone resorption. In this study, to address this point, we used an MMP-9 antisense phosphothiorate oligodeoxynucleotide (S-ODN), which was shown to inhibit the protein synthesis of MMP-9 efficiently. We demonstrated that the antisense S-ODN inhibited osteoclastic pit formation on matrigel-coated dentine slices in a concentration-dependent manner with a maximum reduction of total pit volume by 53% at 10 microM. These results, taken together, suggest that MMP-9 is involved in osteoclastic bone resorption process possibly by facilitating migration of osteoclasts through proteoglican-rich matrices.     

Imbalance of local bone metabolism in inflammatory arthritis and its reversal upon tumor necrosis factor blockade: direct analysis of bone turnover in murine arthritis

Chronic arthritis typically leads to loss of periarticular bone, which results from an imbalance between bone formation and bone resorption. Recent research has focused on the role of osteoclastogenesis and bone resorption in arthritis. Bone resorption cannot be observed isolated, however, since it is closely linked to bone formation and altered bone formation may also affect inflammatory bone loss. To simultaneously assess bone resorption and bone formation in inflammatory arthritis, we developed a histological technique that allows visualization of osteoblast function by in-situ hybridization for osteocalcin and osteoclast function by histochemistry for tartrate-resistant acid phosphatase. Paw sections from human tumor necrosis factor transgenic mice, which develop an erosive arthritis, were analyzed at three different skeletal sites: subchondral bone erosions, adjacent cortical bone channels, and endosteal regions distant from bone erosions. In subchondral bone erosions, osteoclasts were far more common than osteoblasts. In contrast, cortical bone channels underneath subchondral bone erosions showed an accumulation of osteoclasts but also of functional osteoblasts resembling a status of high bone turnover. In contrast, more distant skeletal sites showed only very low bone turnover with few scattered osteoclasts and osteoblasts. Within subchondral bone erosions, osteoclasts populated the subchondral as well as the inner wall, whereas osteoblasts were almost exclusively found along the cortical surface. Blockade of tumor necrosis factor reversed the negative balance of bone turnover, leading to a reduction of osteoclast numbers and enhanced osteoblast numbers, whereas the blockade of osteoclastogenesis by osteoprotegerin also abrogated the osteoblastic response. These data indicate that bone resorption dominates at skeletal sites close to synovial inflammatory tissue, whereas bone formation is induced at more distant sites attempting to counter-regulate bone resorption.     

Imbalance of local bone metabolism in inflammatory arthritis and its reversal upon tumor necrosis factor blockade: direct analysis of bone turnover in murine arthritis

Chronic arthritis typically leads to loss of periarticular bone, which results from an imbalance between bone formation and bone resorption. Recent research has focused on the role of osteoclastogenesis and bone resorption in arthritis. Bone resorption cannot be observed isolated, however, since it is closely linked to bone formation and altered bone formation may also affect inflammatory bone loss. To simultaneously assess bone resorption and bone formation in inflammatory arthritis, we developed a histological technique that allows visualization of osteoblast function by in-situ hybridization for osteocalcin and osteoclast function by histochemistry for tartrate-resistant acid phosphatase. Paw sections from human tumor necrosis factor transgenic mice, which develop an erosive arthritis, were analyzed at three different skeletal sites: subchondral bone erosions, adjacent cortical bone channels, and endosteal regions distant from bone erosions. In subchondral bone erosions, osteoclasts were far more common than osteoblasts. In contrast, cortical bone channels underneath subchondral bone erosions showed an accumulation of osteoclasts but also of functional osteoblasts resembling a status of high bone turnover. In contrast, more distant skeletal sites showed only very low bone turnover with few scattered osteoclasts and osteoblasts. Within subchondral bone erosions, osteoclasts populated the subchondral as well as the inner wall, whereas osteoblasts were almost exclusively found along the cortical surface. Blockade of tumor necrosis factor reversed the negative balance of bone turnover, leading to a reduction of osteoclast numbers and enhanced osteoblast numbers, whereas the blockade of osteoclastogenesis by osteoprotegerin also abrogated the osteoblastic response. These data indicate that bone resorption dominates at skeletal sites close to synovial inflammatory tissue, whereas bone formation is induced at more distant sites attempting to counter-regulate bone resorption.     

Hypothermia inhibits osteoblast differentiation and bone formation but stimulates osteoclastogenesis

It has long been known that core body temperature declines with age, with temperatures of 35.5°C or below common in the elderly. However, the effects of temperature reduction on bone cell function and skeletal homeostasis have been little studied. We investigated the effects of mild hypothermia (35.5°C) and severe hypothermia (34°C) on bone-forming osteoblasts, and bone-resorbing osteoclasts. Formation of 'trabecular' bone structures by rat calvarial osteoblasts was reduced by 75% at 35.5°C and by 95% at 34°C after 14-16 days culture, compared to 37°C. In addition to reductions in osteoblast cell number, expression of mRNAs for Runx2, alkaline phosphatase, osteocalcin and type I collagen were also down-regulated in hypothermia. In contrast, formation of osteoclasts in mononuclear cell cultures derived from mouse marrow, showed a 1.5 to 2-fold stimulation in hypothermia; resorption pit formation was similarly increased. Taken together, these data show that hypothermia exerts reciprocal effects on bone cell function by retarding osteoblast differentiation and bone formation, whilst increasing osteoclastogenesis and thus resorption. These results suggest the possibility that hypothermia in the elderly could potentially have a direct, negative impact on bone metabolism.     

Morphological evidence of reduced bone resorption in the osteosclerotic (oc) mouse

Osteopetrosis, a metabolic bone disease characterized by a generalized sclerosis of the skeleton, is inherited as an autosomal recessive in a number of mammalian species. The pathogenesis of congenital osteopetrosis is mediated by a reduction in bone resorption as a result of decreased osteoclast function. This hypothesis is based on both functional and structural evidence of reduced bone resorption in all mutations examined to date. The present study examined the histology of cartilage and bone, the ultrastructure of osteoclasts, and the morphology of mineralized bone surfaces in a lethal osteopetrotic mutation, the osteosclerotic (oc) mouse. Histologically, epiphyseal cartilage growth plates, especially the hypertrophic zone, are markedly thickened in oc mice and metaphyses contain excessive osteoid, features characteristic of rickets. Transmission electron microscopy revealed that less than one-quarter of osteoclasts in oc mice demonstrated evidence of ruffled border formation compared with three-quarters of the osteoclasts in normal littermates. In mutants, ruffled borders were less elaborate and cytoplasmic processes penetrated into bone surfaces, suggesting that bone may be removed by mechanical rather than by enzymatic means. There was little morphological evidence of cartilage degradation and broad laminae limitantes persisted in mutants. Mineralized surfaces that undergo resorption in normal mice showed no evidence of bone resorption by scanning EM in mutants. The presence of a rachitic condition, the observations of reduced bone resorption, and the possible contribution of undermineralized matrices to decreased bone resorption are characteristics of the osteosclerotic mutation which suggest that it is a unique osteopetrotic mutant in which to study both the development and regulation of skeletal metabolism.     

Features of mono- and multinucleated bone resorbing cells of the zebrafish Danio rerio and their contribution to skeletal development, remodeling, and growth.

To provide basic data about bone resorbing cells in the skeleton during the life cycle of Danio rerio, larvae, juveniles, and adults (divided into six age groups) were studied by histological procedures and by demonstration of the osteoclast marker enzyme tartrate-resistant acid phosphatase (TRAP). Special attention was paid to the lower jaw, which is a standard element for fish bone studies. The presence of osteoclasts at endosteal surfaces of growing bones of all animals older than 20 days reveals that resorption is an important part of zebrafish skeletal development. The first bone-resorbing cells to form are mononucleated. They appear in 20-day-old animals concurrently in the craniofacial skeleton and vertebral column. Mononucleated osteoclasts are predominant in juveniles. Regional differences characterize the appearance of osteoclasts; at thin skeletal elements (neural arches, nasal) mononucleated osteoclasts are predominant even in adults. Multinucleated bone-resorbing cells were first observed in 40-day-old animals and are the predominant osteoclast type of adults. Both mono- and multinucleated osteoclasts contribute to allometric bone growth but multinucleated osteoclasts are also involved in lacunar bone resorption and repeated bone remodeling. Resorption of the dentary follows the pattern described above (mononucleated osteoclasts precede multinucleated cells) and includes the partial removal of Meckel's cartilage. Bone marrow spaces created by resorption are usually filled with adipose tissue. In conclusion, bone resorption is primarily subjected to the demands of growth, the appearance of mono- and multinucleated osteoclasts is site- and age-related, and bone remodeling occurs. The results are discussed in relation to findings in other teleosts and in mammals.     

Brefeldin A inhibits osteoclastic bone resorption through induction of apoptosis

Brefeldin A (BFA), a fungal metabolite with a macrocyclic lactone structure, has been developed for the treatment of cancer, and its major biological activity is the inhibition of intracellular protein transport from the endoplasmic reticulum to the cis-Golgi apparatus. In this study, we investigated the effect of BFA on osteoclastic pit formation in vitro. BFA reduced pit formation in a concentration-dependent manner, and the IC50 values on the pit number and the pit volume were 11.3 +/- 2.2 and 13.3 +/- 2.0 nM, respectively. In parallel with the inhibitory effect on pit formation, BFA also reduced the cell viability of osteoclasts-enriched bone cells with an IC50 value of 13.9 +/- 2.2 nM. These results suggest that the inhibition of bone resorption by BFA is caused by the induction of osteoclast cell death. BFA at a concentration of 100 nM induced DNA fragmentation in purified osteoclasts, assessed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and DNA ladder formation, demonstrating that BFA induces cell death of osteoclasts in an apoptotic manner. In addition, the accumulation of p53 proteins to the nuclei was observed in the osteoclasts treated with 100 nM BFA. These results, taken together, suggest that BFA inhibits osteoclastic bone resorption by inducing apoptosis in osteoclasts through a p53-dependent mechanism.     

Bisphosphonates: new therapeutic agents for the treatment of bone tumors

Bisphosphonates (BPs) have been used successfully for many years to reduce the skeletal complications associated with the benign and malignant bone diseases that are characterized by enhanced osteoclastic bone resorption. Until recently, it was thought that the clinical efficacy of BPs in the treatment of cancer patients with bone metastases was purely a result of the inhibition of osteoclast-mediated bone resorption. However, recent studies have demonstrated that BPs inhibit the growth, attachment and invasion of cancer cells in culture and promote their apoptosis. These results suggest that BPs are also anti-cancer agents, raising the possibility that BPs could inhibit cancer-cell colonization in visceral organs. However, results from clinical trials are conflicting, and whether BPs possess anti-cancer effects or not remains controversial.     

Antithetic effects of ryanodine and ruthenium red on osteclast-mediated bone resorption and intracellular calcium concentrations

In the process of bone remodeling, osteoclasts are responsible for resorption of bone. High levels of intracellular calcium decrease the bone resorbing activity of osteoclasts and increase detachment of osteoclasts from the bone surface. The regulatory role of intracellular calcium in bone resorption is not clearly understood. To understand this phenomenon, we studied the effects of the intracellular calcium modulators ryanodine and ruthenium red on bone resorption using the disaggregated osteoclast pit assay. Changes in intracellular calcium concentrations after treatment with these compounds were detected with the fluoroprobe fura2. With ryanodine, a significant, dose-dependent decrease in bone resorption was detected. This inhibition of bone resorption was reversible upon the removal of ryanodine. Ryanodine increased intracellular calcium concentrations, suggesting that the mechanism of inhibition by ryanodine was via alterations in intracellular stores of calcium. After treatment with ruthenium red, osteoclasts resorbed significantly more bone compared to vehicle-treated cells. This increase in bone resorption correlated with a decrease in intracellular calcium concentrations. The addition of parathyroid hormone or ruthenium red to osteoclast cultures containing ryanodine did not attenuate the decrease in bone resorption caused by ryanodine, suggesting that the mechanism of ryanodine inhibition of bone resorption may involve the “locking” of a calcium channel in an open position. © 1995 Wiley-Liss, Inc.     

A comparative view on mechanisms and functions of skeletal remodelling in teleost fish, with special emphasis on osteoclasts and their function

Resorption and remodelling of skeletal tissues is required for development and growth, mechanical adaptation, repair, and mineral homeostasis of the vertebrate skeleton. Here we review for the first time the current knowledge about resorption and remodelling of the skeleton in teleost fish, the largest and most diverse group of extant vertebrates. Teleost species are increasingly used in aquaculture and as models in biomedical skeletal research. Thus, detailed knowledge is required to establish the differences and similarities between mammalian and teleost skeletal remodelling, and between distantly related species such as zebrafish (Danio rerio) and medaka (Oryzias latipes). The cellular mechanisms of differentiation and activation of osteoclasts and the functions of teleost skeletal remodelling are described. Several characteristics, related to skeletal remodelling, distinguish teleosts from mammals. These characteristics include (a) the absence of osteocytes in most species; (b) the absence of haematopoietic bone marrow tissue; (c) the abundance of small mononucleated osteoclasts performing non‐lacunar (smooth) bone resorption, in addition to or instead of multinucleated osteoclasts; and (d) a phosphorus‐ rather than calcium‐driven mineral homeostasis (mainly affecting the postcranial dermal skeleton). Furthermore, (e) skeletal resorption is often absent from particular sites, due to sparse or lacking endochondral ossification. Based on the mode of skeletal remodelling in early ontogeny of all teleosts and in later stages of development of teleosts with acellular bone we suggest a link between acellular bone and the predominance of mononucleated osteoclasts, on the one hand, and cellular bone and multinucleated osteoclasts on the other. The evolutionary origin of skeletal remodelling is discussed and whether mononucleated osteoclasts represent an ancestral type of resorbing cells. Revealing the differentiation and activation of teleost skeletal resorbing cells, in the absence of several factors that trigger mammalian osteoclast differentiation, is a current challenge. Understanding which characters of teleost bone remodelling are derived and which characters are conserved should enhance our understanding of the process in fish and may provide insights into alternative pathways of bone remodelling in mammals.