Drosophila transforming growth factor beta superfamily proteins induce endochondral bone formation in mammals.

Endochondral bone formation was induced in postnatal rats by implantation of demineralized rat bone matrix. Corresponding control tissue was generated by implanting inactive extracted bone matrix, which did not induce bone formation. At various times, implants were removed and sequentially extracted with guanidine hydrochloride, and then EDTA and guanidine hydrochloride. Transforming growth factor beta (TGF beta) in the extracts was quantitated by a radioreceptor assay. TGF beta was present in demineralized bone matrix before implantation, and the concentration had decreased by 1 d after implantation. Thereafter, TGF beta was undetectable by radioreceptor assay until day 9. From day 9-21 the TGF beta was extracted only after EDTA demineralization, indicating tight association with the mineralized matrix. During this time, the content of TGF beta per milligram soluble protein rose steadily and remained high through day 21. This increased concentration correlated with the onset of vascularization and calcification of cartilage. TGF beta was detected only between days 3-9 in the controls; i.e., non-bone-forming implants. Immunolocalization of TGF beta in bone-forming implants revealed staining of inflammatory cells at early times, followed later by staining of chondrocytes in calcifying cartilage and staining of osteoblasts. The most intense staining of TGF beta was found in calcified cartilage and mineralized bone matrix, again indicating preferential compartmentalization of TGF beta in the mineral phase. In contrast to the delayed expression of TGF beta protein, northern blot analysis showed TGF beta mRNA in implants throughout the sequence of bone formation. The time-dependent accumulation of TGF beta when cartilage is being replaced by bone in this in vivo model of bone formation suggests that TGF beta may play a role in the regulation of ossification during endochondral bone development.

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Systemic administration of transforming growth factor-beta 2 prevents the impaired bone formation and osteopenia induced by unloading in rats.

Journal of Clinical Investigation ◽

10.1172/jci118158 ◽

1995 ◽

Vol 96 (3) ◽

pp. 1245-1253 ◽

Cited By ~ 59

Author(s):

M Machwate ◽

E Zerath ◽

X Holy ◽

M Hott ◽

D Godet ◽

...

Keyword(s):

Growth Factor ◽

Bone Formation ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Systemic Administration ◽

Growth Factor Beta ◽

Beta 2

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Bone formation in Transforming Growth Factor beta-1-loaded titanium fiber mesh implants

Clinical Oral Implants Research ◽

10.1034/j.1600-0501.2002.130112.x ◽

2002 ◽

Vol 13 (1) ◽

pp. 94-102 ◽

Cited By ~ 70

Author(s):

Johan W.M. Vehof ◽

Marcus T.U. Haus ◽

Anja E. De Ruijter ◽

John A. Jansen ◽

Paul H.M. Spauwen

Keyword(s):

Growth Factor ◽

Bone Formation ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Growth Factor Beta ◽

Fiber Mesh

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The effects of age on the response of rabbit periosteal osteoprogenitor cells to exogenous transforming growth factor-beta 2

Journal of Cell Science ◽

10.1242/jcs.107.2.499 ◽

1994 ◽

Vol 107 (2) ◽

pp. 499-516 ◽

Cited By ~ 2

Author(s):

M.A. Critchlow ◽

Y.S. Bland ◽

D.E. Ashhurst

Keyword(s):

Growth Factor ◽

Bone Formation ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Experimental Period ◽

Osteoprogenitor Cells ◽

Periosteal Bone Formation ◽

Growth Factor Beta ◽

Beta 2 ◽

And Cartilage

Additional bone and cartilage are formed if transforming growth factor-beta is injected into the periosteum of calvariae or long bones. To investigate this further, transforming growth factor-beta 2 was injected into the periosteum of the tibia of 3-day-old, 3-month-old and 2-year-old rabbits. In all instances, there was an increase in proliferation of the cells of the cambial layer of the periosteum, that is, the osteoprogenitor cells, and breakdown of the fibrous layer. Oedema was induced in the surrounding connective tissues. Over the experimental period the normal neonatal tibia is undergoing rapid growth; there is periosteal bone formation and endosteal resorption. In the experimental neonatal tibiae, an increase in periosteal bone formation is seen after three injections of 20 ng of transforming growth factor-beta 2, which is accompanied by cartilage after five injections; the amounts of induced bone and cartilage increase with the number of injections. The chondrocytes hypertrophy after 4 days and the cartilage is replaced by bone endochondrally. In contrast, after seven injections of 20 ng transforming growth factor-beta 2, there is only a small amount of new bone on the 3-month-old tibia and none on the 2-year-old tibia. One day after seven injections of 200 ng transforming growth factor-beta 2, there is a small amount of bone formation, while seven days after cartilage is found as small discrete nodules on the 3-month-old tibia, but as small areas within the bone on the 2-year-old tibia. It is concluded that the primary effect of transforming growth factor-beta 2 in this experimental model is to increase the proliferative rate of the osteoprogenitor cells in the periosteum. It is argued that transforming growth factor-beta 2 does not initiate osteoblastic or chondrocytic differentiation of osteoprogenitor cells. It is suggested that their differentiation is controlled by the local environment, in particular, the vascularity and locally circulating growth factors.

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Transforming growth factor-beta and the initiation of chondrogenesis and osteogenesis in the rat femur.

The Journal of Cell Biology ◽

10.1083/jcb.110.6.2195 ◽

1990 ◽

Vol 110 (6) ◽

pp. 2195-2207 ◽

Cited By ~ 544

Author(s):

M E Joyce ◽

A B Roberts ◽

M B Sporn ◽

M E Bolander

Keyword(s):

Growth Factor ◽

Bone Formation ◽

Fracture Healing ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Tgf Beta ◽

Intramembranous Bone ◽

Growth Factor Beta ◽

Beta 2 ◽

Intramembranous Bone Formation

We have investigated the ability of exogenous transforming growth factor-beta (TGF-beta) to induce osteogenesis and chondrogenesis, critical events in both bone formation and fracture healing. Daily injections of TGF-beta 1 or 2 into the subperiosteal region of newborn rat femurs resulted in localized intramembranous bone formation and chondrogenesis. After cessation of the injections, endochondral ossification occurred, resulting in replacement of cartilage with bone. Gene expression of type II collagen and immunolocalization of types I and II collagen were detected within the TGF-beta-induced cartilage and bone. Moreover, injection of TGF-beta 2 stimulated synthesis of TGF-beta 1 in chondrocytes and osteoblasts within the newly induced bone and cartilage, suggesting positive autoregulation of TGF-beta. TGF-beta 2 was more active in vivo than TGF-beta 1, stimulating formation of a mass that was on the average 375% larger at a comparable dose (p less than 0.001). With either TGF-beta isoform, the dose of the growth factor determined which type of tissue formed, so that the ratio of cartilage formation to intramembranous bone formation decreased as the dose was lowered. For TGF-beta 1, reducing the daily dose from 200 to 20 ng decreased the cartilage/intramembranous bone formation ratio from 3.57 to zero (p less than 0.001). With TGF-beta 2, the same dose change decreased the ratio from 3.71 to 0.28 (p less than 0.001). These data demonstrate that mesenchymal precursor cells in the periosteum are stimulated by TGF-beta to proliferate and differentiate, as occurs in embryologic bone formation and early fracture healing.

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