When cancer metastasizes to bone, considerable pain and deregulated bone remodelling occurs, greatly diminishing the possibility of cure. Metastasizing tumour cells mobilize and sculpt the bone microenvironment to enhance tumour growth and to promote bone invasion. Understanding the crucial components of the bone microenvironment that influence tumour localization, along with the tumour-derived factors that modulate cellular and protein matrix components of bone to favour tumour expansion and invasion, is central to the pathophysiology of bone metastases. Basic findings of tumour–bone interactions have uncovered numerous therapeutic opportunities that focus on the bone microenvironment to prevent and treat bone metastases.

Cancer to bone: a fatal attraction

Traumatic brain injury (TBI) is seen by the insurance industry and many health care providers as an “event.” Once treated and provided with a brief period of rehabilitation, the perception exists that patients with a TBI require little further treatment and face no lasting effects on the central nervous system or other organ systems. In fact, TBI is a chronic disease process, one that fits the World Health Organization definition as having one or more of the following characteristics: it is permanent, caused by non-reversible pathological alterations, requires special training of the patient for rehabilitation, and/or may require a long period of observation, supervision, or care. TBI increases long-term mortality and reduces life expectancy. It is associated with increased incidences of seizures, sleep disorders, neurodegenerative diseases, neuroendocrine dysregulation, and psychiatric diseases, as well as non-neurological disorders such as sexual dysfunction, bladder and bowel incontinence, and...

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Traumatic Brain Injury: A Disease Process, Not an Event

Since the identification in 1988 of bone morphogenetic protein 2 (BMP2) as a potent inducer of bone and cartilage formation, BMP superfamily signalling has become one of the most heavily investigated topics in vertebrate skeletal biology. Whereas a large part of this research has focused on the roles of BMP2, BMP4 and BMP7 in the formation and repair of endochondral bone, a large number of BMP superfamily molecules have now been implicated in almost all aspects of bone, cartilage and joint biology. As modulating BMP signalling is currently a major therapeutic target, our rapidly expanding knowledge of how BMP superfamily signalling affects most tissue types of the skeletal system creates enormous potential to translate basic research findings into successful clinical therapies that improve bone mass or quality, ameliorate diseases of skeletal overgrowth, and repair damage to bone and joints. This Review examines the genetic evidence implicating BMP superfamily signalling in vertebrate bone and joint development, discusses a selection of human skeletal disorders associated with altered BMP signalling and summarizes the status of modulating the BMP pathway as a therapeutic target for skeletal trauma and disease.

BMP signalling in skeletal development, disease and repair

Bone morphogenetic proteins (BMPs) are cytokines with a strong effect on bone and cartilage growth and with important roles during embryonic patterning and early skeletal formation. BMPs have promising potential for clinical bone and cartilage repair, working as powerful bone-inducing components in diverse tissue-engineering products. Synthetic polymers, natural origin polymers, inorganic materials and composites may be used as carriers for the delivery of BMPs. Carriers range from nanoparticles to complex three-dimensional (3D) scaffolds, membranes for tissue-guided regeneration, biomimetic surfaces and smart thermosensitive hydrogels. Current clinical uses include spinal fusion, healing of long bone defects and craniofacial and periodontal applications, amongst others. BMP-2 and BMP-7 have recently received approval by the US Food and Drug Administration (FDA) for specific clinical cases, delivered in absorbable collagen sponges. Considering the expanding number of publications in the field of BMPs, there are prospects of a brilliant future in the field of regenerative medicine of bone and cartilage with the use of BMPs.

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Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery)

通过复习异位骨化的相关文献,详细介绍了异位骨化的发病机制、分类、发生率、分型、发病因素、临床表现、诊断、预防及治疗方法.异位骨化是指在正常情况下没有骨组织的软组织内形成的新生骨,在组织学上,成熟的异位骨化与骨痂一致.其形成一般需三个条件:①成骨诱导物;②成骨的前体细胞;③允许成骨的组织环境.早期表现包括关节周围疼痛、发热、红肿,逐渐出现关节活动受限.三相核素骨扫描是早期检测异位骨化的最敏感指标,并可以判断病变的活动性和成熟度.非甾体类消炎药(NSAIDs)是目前公认的预防人工髋关节置换和髋臼骨折术后异位骨化形成的最有效的药物.手术切除是异位骨化形成后导致严重关节功能障碍患者的唯一治疗手段。

Heterotopic ossification

The role of bone morphogenetic proteins (BMPs) in bone healing has been shown in numerous animal models. To date, at least 20 BMPs have been identified, some of which have been shown in vitro to stimulate the process of stem cell differentiation into osteoblasts in human and animal models. Having realized the osteoinductive properties of BMPs and having identified their genetic sequences, recombinant gene technology has been used to produce BMPs for clinical application - most commonly, as alternatives or adjuncts in the treatment of cases in which fracture healing is compromised. BMP-2 and BMP-7 are approved for clinical use in open fractures of long bones, non-unions and spinal fusion. However, despite significant evidence of their potential benefit to bone repair and regeneration in animal and preclinical studies, there is, to date, a dearth of convincing clinical trials. The purpose of this paper is to give a brief overview of BMPs and to critically review the clinical data currently available on the use of BMP-2 and BMP-7 in fracture healing.

Bone morphogenetic proteins in clinical applications.

Primary osteoporosis is an age-related disease characterized by an imbalance in bone homeostasis. While the resorptive aspect of the disease has been studied intensely, less is known about the anabolic part of the syndrome or presumptive deficiencies in bone regeneration. Multipotent mesenchymal stem cells (MSC) are the primary source of osteogenic regeneration. In the present study we aimed to unravel whether MSC biology is directly involved in the pathophysiology of the disease and therefore performed microarray analyses of hMSC of elderly patients (79–94 years old) suffering from osteoporosis (hMSC-OP). In comparison to age-matched controls we detected profound changes in the transcriptome in hMSC-OP, e.g. enhanced mRNA expression of known osteoporosis-associated genes (LRP5, RUNX2, COL1A1) and of genes involved in osteoclastogenesis (CSF1, PTH1R), but most notably of genes coding for inhibitors of WNT and BMP signaling, such as Sclerostin and MAB21L2. These candidate genes indicate intrinsic deficiencies in self-renewal and differentiation potential in osteoporotic stem cells. We also compared both hMSC-OP and non-osteoporotic hMSC-old of elderly donors to hMSC of ∼30 years younger donors and found that the transcriptional changes acquired between the sixth and the ninth decade of life differed widely between osteoporotic and non-osteoporotic stem cells. In addition, we compared the osteoporotic transcriptome to long term-cultivated, senescent hMSC and detected some signs for pre-senescence in hMSC-OP.

Our results suggest that in primary osteoporosis the transcriptomes of hMSC populations show distinct signatures and little overlap with non-osteoporotic aging, although we detected some hints for senescence-associated changes. While there are remarkable inter-individual variations as expected for polygenetic diseases, we could identify many susceptibility genes for osteoporosis known from genetic studies. We also found new candidates, e.g. MAB21L2, a novel repressor of BMP-induced transcription. Such transcriptional changes may reflect epigenetic changes, which are part of a specific osteoporosis-associated aging process.

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The Transcriptional Profile of Mesenchymal Stem Cell Populations in Primary Osteoporosis Is Distinct and Shows Overexpression of Osteogenic Inhibitors

Medium-term results after complex intra-articular fractures of the tibial plateau

Purpose
The purpose of this study was to characterise the biomechanical properties of the seven hole superior anterior clavicle LCP (locking compression plate) and to compare these with the properties of commonly applied implants used for the stabilisation of clavicular midshaft fractures such as the locking 7- and ten hole reconstruction plate.

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Biomechanical comparison of the Locking Compression superior anterior clavicle plate with seven and ten hole reconstruction plates in midshaft clavicle fracture stabilisation

Background: Patients with a traumatic brain injury (TBI) and bone fractures often show an enhanced fracture healing, as well as an increased incidence of heterotopic ossifications (HO). It has been suggested that unknown osteoinductive factors may be released by the injured brain into the systemic blood circulation and act peripherally on the affected tissues. The aim of this study was to investigate whether serum from TBI patients is osteoinductive.



Methods:  Sixty-one consecutive patients were classified into four groups: TBI and long-bone fracture (group I, n = 12), isolated severe TBI (group II, n = 21), isolated long-bone fracture (group III, n = 19) and controls (group IV, n = 9). Blood samples were collected at 6, 24, 72 and 168 h post-injury. The osteogenic potential was determined by measuring the in vitro proliferation rate of the human fetal osteoblastic cell line hFOB1.19, and primary human osteoblasts. Additionally, serum induced osteoblastic differentiation was assessed by measuring the mRNA expression of specific osteoblastic markers, including alkaline phosphatase, runt-related transcription factor 2, cathepsin K and serine protease 7.



Results:  The sera of group I induced a higher mean proliferation rate of primary human osteoblasts at all time points of sampling than group III (P < 0.05). Group I had a higher mean proliferation rate of hFOB1.19 cells than all other groups at 6, 24 and 72 h post-injury (P < 0.05). The expression of alkaline phosphatase, cathepsin K and runt-related transcription factor 2 mRNA was increased in group I compared with group III and serine protease 7 was exclusively expressed in group I.



Conclusion:  The study results strongly support a humoral mechanism in enhanced fracture healing and the induction of HO after TBI. Increased proliferation of osteoblastic cells and an accelerated differentiation of osteoprogenitor cells may be responsible for increased osteogenesis in TBI.

Sönke P. Frey

Papers

Bone morphogenetic proteins in clinical applications.

The Transcriptional Profile of Mesenchymal Stem Cell Populations in Primary Osteoporosis Is Distinct and Shows Overexpression of Osteogenic Inhibitors

Medium-term results after complex intra-articular fractures of the tibial plateau

Biomechanical comparison of the Locking Compression superior anterior clavicle plate with seven and ten hole reconstruction plates in midshaft clavicle fracture stabilisation

Serum-mediated osteogenic effect in traumatic brain-injured patients.