Tendon disorders are frequent and are responsible for substantial morbidity both in sports and in the workplace. Tendinopathy, as opposed to tendinitis or tendinosis, is the best generic descriptive term for the clinical conditions in and around tendons arising from overuse. Tendinopathy is a difficult problem requiring lengthy management, and patients often respond poorly to treatment. Preexisting degeneration has been implicated as a risk factor for acute tendon rupture. Several physical modalities have been developed to treat tendinopathy. There is limited and mixed high-level evidence to support the, albeit common, clinical use of these modalities. Further research and scientific evaluation are required before biological solutions become realistic options.

http://health120years.com/cn/pdf/hd_tendonopathy_tendinosis_healing_repair.pdf

Tendon injury and tendinopathy: healing and repair.

•: Growth factors (bone morphogenetic protein, transforming growth factor-beta, fibroblast growth factor, platelet-derived growth factor, and insulin-like growth factor) are proteins secreted by cells that act on the appropriate target cell or cells to carry out a specific action.

•: Because growth factors are expressed during different phases of fracture-healing, it has been thought that they may serve as potential therapeutic agents to enhance bone repair.

•: The selection of an appropriate carrier or delivery system for a particular growth factor is essential in order to induce a specific biologic effect.

•: There are a number of potential clinical applications for growth factors in the enhancement of bone repair, including acceleration of fracture-healing, treatment of established nonunions, enhancement of primary spinal fusion or treatment of established pseudarthrosis of the spine, and as one element of a comprehensive tissue-engineering strategy that could include gene therapy to treat large bone-loss problems.

Growth factors are proteins that serve as signaling agents for cells. They function as part of a vast cellular communications network that influences such critical functions as cell division, matrix synthesis, and tissue differentiation. The results of experimental studies have established that growth factors play an important role in bone and cartilage formation, fracture-healing, and the repair of other musculoskeletal tissues. Recently, with the advent of recombinant proteins, there has been considerable interest in the use of growth factors as therapeutic agents in the treatment of skeletal injuries. As growth factors become available as therapeutic agents, it is essential that orthopaedic surgeons understand their biological characteristics and clinical potential. The purpose of this review is to define the mechanisms of action, functions, and potential clinical applications of a variety of growth factors that may be used clinically to treat problems associated with the repair of bone.

Growth factors are proteins secreted …

The role of growth factors in the repair of bone. Biology and clinical applications.

Background:Bone morphogenic proteins (BMPs) are known to promote osteogenesis, and clinical trials are currently underway to evaluate the ability of certain BMPs to promote fracture-healing and spinal fusion. The optimal BMPs to be used in different clinical applications have not been elucidated, an

Osteogenic activity of the fourteen types of human bone morphogenetic proteins (bmps)

The repair of large bone defects remains a major clinical orthopaedic challenge. Bone is a highly vascularised tissue reliant on the close spatial and temporal connection between blood vessels and bone cells to maintain skeletal integrity. Angiogenesis thus plays a pivotal role in skeletal development and bone fracture repair. Current procedures to repair bone defects and to provide structural and mechanical support include the use of grafts (autologous, allogeneic) or implants (polymeric or metallic). These approaches face significant limitations due to insufficient supply, potential disease transmission, rejection, cost and the inability to integrate with the surrounding host tissue. The engineering of bone tissue offers new therapeutic strategies to aid musculoskeletal healing. Various scaffold constructs have been employed in the development of tissue-engineered bone; however, an active blood vessel network is an essential pre-requisite for these to survive and integrate with existing host tissue. Combination therapies of stem cells and polymeric growth factor release scaffolds tailored to promote angiogenesis and osteogenesis are under evaluation and development actively to stimulate bone regeneration. An understanding of the cellular and molecular interactions of blood vessels and bone cells will enhance and aid the successful development of future vascularised bone scaffold constructs, enabling survival and integration of bioengineered bone with the host tissue. The role of angiogenic and osteogenic factors in the adaptive response and interaction of osteoblasts and endothelial cells during the multi step process of bone development and repair will be highlighted in this review, with consideration of how some of these key mechanisms can be combined with new developments in tissue engineering to enable repair and growth of skeletal fractures. Elucidation of the processes of angiogenesis, osteogenesis and tissue engineering strategies offer exciting future therapeutic opportunities for skeletal repair and regeneration in orthopaedics.

/pdf/osteogenesis-and-angiogenesis-the-potential-for-engineering-587jt2awl8.pdf

Osteogenesis and angiogenesis: the potential for engineering bone.

Over the last decade the identification of mutations in the receptors for fibroblast growth factors (FGFs) has defined essential roles for FGF signaling in both endochondral and intramembranous bone development. FGF signaling pathways are essential for the earliest stages of limb development and throughout skeletal development. In this review, we examine the role of FGF signaling in bone development and in human genetic diseases that affect bone development. We also explore what is presently known about how FGF signaling pathways interact with other major signaling pathways that regulate chondrogenesis and osteogenesis. Overview of skeletal development Skeletal elements are formed through two distinct developmental processes. Endochondral ossification gives rise to long bones that comprise the appendicular skeleton, facial bones, vertebrae, and the lateral medial clavicles. Intramembranous ossification gives rise to the flat bones that comprise the cranium and medial clavicles. Both types of ossification involve an initial condensation of mesenchyme and the eventual formation of calcified bone. However, intramembranous bone formation accomplishes this directly, whereas endochondral ossification incorporates an intermediate step in which a cartilaginous template regulates the growth and patterning of the developing skeletal element. Development of endochondral bones initiates shortly after the formation of the limb bud with the condensation of loose mesenchyme, marked by expression of type

/pdf/fgf-signaling-pathways-in-endochondral-and-intramembranous-1ju3vm24l9.pdf

FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease.

Single local injection of recombinant fibroblast growth factor‐2 stimulates healing of segmental bone defects in rabbits

Bone lengthening by callotasis is one of the most useful methods not only for the treatment of short extremities but also for extensive bone defects; however, the procedure takes a long time especially for the consolidation of the distracted callus. In this study, effects of a single local injection of recombinant human fibroblast growth factor-2 (FGF-2 or basic FGF) on callotasis bone lengthening were examined in rabbits. Ten days after the osteotomy at the middle of the tibia and the installment of an external fixator, the osteotomized site was distracted at a rate of 1.4 mm/day for 7 days, resulting in 9.8 mm lengthening. On the final day of distraction, 200 μg of FGF-2 in 150 μl of saline solution or vehicle alone was injected into the center of the distracted callus. Injection of FGF-2 increased bone formation at the distracted callus radiologically and histologically. A significant effect on bone mineral content (BMC) at the callus was observed as early as 2 weeks, and FGF-2 increased the BMC about twofold at 5 weeks after a normal remodeling process. We conclude that the callotasis method in combination with FGF-2 injection at the consolidation step could be clinically beneficial to shorten the bone lengthening period.

Stimulation of bone formation by recombinant fibroblast growth factor-2 in callotasis bone lengthening of rabbits.

arthritis (RA) patients witn different severities of joint destruction on osteoclastogenesis and bone resorption. Methods. Synovial fluid was harvested from the knee joints of 59 RA patients and 37 osteoarthritis (OA) patients. RA patients with Larsen's knee grade 1-3 were classified as mild RA (n = 30) and those with grade 4 or 5 as severe RA (n = 29). Cytokine concentrations in synovial fluid were measured by ELISA. Osteoclastogenesis was measured by tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cell (MNC) formation in a co-culture of mouse osteoblastic cells and bone marrow cells, and bone resorption by 45 Ca release from pre-labelled cultured neonatal mouse calvariae. Results. The synovial fluid of severe RA patients significantly stimulated TRAP-positive MNC formation and 45 Ca release compared to those of mild RA and OA patients. Among the bone-resorptive cytokines fibroblast growth factor-2 (FGF-2), tumour necrosis factor alpha (TNF-α), interleukin-1α (IL-1α), IL-6 and soluble IL-6 receptor (sIL-6R), only FGF-2 concentration in the synovial fluid was positively correlated to Larsen's grade, and severe RA patients showed significantly higher FGF-2 concentrations than mild RA patients. Osteoclastogenesis in a co-culture system which was stimulated by the synovial fluid of severe RA patients was significantly inhibited by a neutralizing antibody against FGF-2 and this inhibition was stronger than antibodies against other cytokines. Conclusion. The increase in endogenous FGF-2 levels in the synovial fluid of RA patients may play a role in the joint destruction by inducing osteoclastogenesis.

Involvement of fibroblast growth factor-2 in joint destruction of rheumatoid arthritis patients

Stimulation of bone formation by intraosseous application of recombinant basic fibroblast growth factor in normal and ovariectomized rabbits

Fibroblast growth factor 2 (FGF-2 or basic FGF) is known to show variable actions on bone formation and bone resorption This study was undertaken to elucidate the mechanisms whereby FGF-2 affects bone metabolism, especially bone resorption, using three different culture systems FGF-2 at 10(-9) M and higher concentrations induced osteoclastic cell formation in the coculture system of mouse osteoblastic cells and bone marrow cells, and this induction was abrogated by nonsteroidal anti-inflammatory drugs (NSAIDs) 45Ca release from prelabeled cultured mouse calvariae stimulated by FGF-2 (10(-8) M) was also inhibited by NSAIDs, and the inhibition was stronger by NSAIDs, which are more selective for inhibition of cyclooxygenase 2 (COX-2) than COX-1, suggesting the mediation of COX-2 induction COX-2 was highly expressed and its messenger RNA (mRNA) level was stimulated by FGF-2 in osteoblastic cells whereas it was undetectable or not stimulated by FGF-2 in cells of osteoclast lineage To further investigate the direct actions of FGF-2 on osteoclasts, resorbed pit formation was compared between cultures of purified osteoclasts and unfractionated bone cells from rabbit long bones FGF-2 (> or = 10(-12) M) stimulated resorbed pit formation by purified osteoclasts with a maximum effect of 20-fold at 10(-11) M, and no further stimulation was observed at higher concentrations However, FGF-2 at 10(-9) M - 10(-8) M stimulated resorbed pit formation by unfractionated bone cells up to 97-fold NS-398, a specific COX-2 inhibitor, did not affect the FGF-2 stimulation on purified osteoclasts but inhibited that on unfractionated bone cells We conclude that FGF-2 at low concentrations (> or =10(-12) M) acts directly on mature osteoclasts to resorb bone moderately, whereas at high concentrations (> or = 10(-9) M) it acts on osteoblastic cells to induce COX-2 and stimulates bone resorption potently

https://asbmr.onlinelibrary.wiley.com/doi/pdf/10.1359/jbmr.2000.15.3.466

Hiroshi Kawaguchi

Papers

Single local injection of recombinant fibroblast growth factor‐2 stimulates healing of segmental bone defects in rabbits

Stimulation of bone formation by recombinant fibroblast growth factor-2 in callotasis bone lengthening of rabbits.

Involvement of fibroblast growth factor-2 in joint destruction of rheumatoid arthritis patients

Stimulation of bone formation by intraosseous application of recombinant basic fibroblast growth factor in normal and ovariectomized rabbits

Direct and indirect actions of fibroblast growth factor 2 on osteoclastic bone resorption in cultures.