Chondrogenesis Just Ain't What It Used to Be

Chondrogenesis just ain’t what it used to be Gerard Karsenty J Clin Invest. 2001;107(4):405-407. https://doi.org/10.1172/JCI12294. Commentary Most of the vertebrate skeleton forms by endochondral ossification, a multistep process that involves two successive cell- differentiation processes. Initially, following mesenchymal cell condensation, a cartilaginous scaffold forms that is later replaced by bone matrix. Under the control of transcription factors of the Sox family, these mesenchymal cells differentiate first into type II collagen–producing cells that proliferate until the shape of the future bone is established (1, 2). Subsequently, cells located at the center of this structure differentiate further to form hypertrophic chondrocytes, which synthesize a cartilaginous matrix that eventually calcifies. At the same time, the most mature hypertrophic chondrocytes undergo apoptosis, allowing the corresponding area to be invaded by blood vessels, and both multinucleate, matrix- resorbing cells and differentiated osteoblasts appear. The cartilaginous matrix is then degraded and replaced by a bone matrix secreted by osteoblasts. Once this process is completed, the only cartilaginous structures remaining are the growth plate cartilages at the two distal ends of the bone. There, chondrocytes at each stage of differentiation — resting, proliferating, and hypertrophic chondrocytes — are arrayed in a linear succession from the most distal to the most medial regions. This growth plate cartilage therefore offers a powerful model for studying cell differentiation in situ. Two mechanisms have been generally proposed to explain how chondrocytes and osteoblasts could emerge successively from the same […] Find the latest version: https://jci.me/12294/pdf Chondrogenesis just ain’t what it Commentary used to be See related article Volume 107, Number 3, pages 295–304. Gerard Karsenty Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030-4009, USA. Phone: (713) 798-5489; Fax: (713) 798-1465; E-mail: [email protected]. Most of the vertebrate skeleton forms later differentiating into osteoblasts. A drocyte hypertrophy. Schipani et al. by endochondral ossification, a multi- second, related issue concerns the extended these studies, demonstrating step process that involves two succes- genetic regulation of the different steps that the chondrocyte-specific, consti- sive cell-differentiation processes. Ini- of endochondral ossification, chondro- tutive expression of PPR in mice caus- tially, following mesenchymal cell genesis, and bone morphogenesis. es a delay in conversion of the prolif- condensation, a cartilaginous scaffold Mostly based on mouse genetic experi- erative chondrocyte into the forms that is later replaced by bone ments, a number of recent studies, hypertrophic chondrocyte. This phe- matrix. Under the control of tran- including the paper by Chung et al. (3) notype mimics the short-limb scription factors of the Sox family, in a recent issue of the JCI, have estab- dwarfism seen in the genetic disorder these mesenchymal cells differentiate lished the cascade of events triggering Jansen metaphyseal chondrodysplasia, first into type II collagen–producing each of these processes and have identi- which is caused by activating muta- cells that proliferate until the shape of fied key factors required in their regu- tions in the human PPR gene (7, 8). the future bone is established (1, 2). lation (Figure 1). This first set of studies also brought Subsequently, cells located at the cen- to light a possible link between the ter of this structure differentiate fur- Hypertrophic chondrocytes and presence of hypertrophic chondrocytes ther to form hypertrophic chondro- Indian hedgehog in skeletal and vascular invasion. This direct rela- cytes, which synthesize a cartilaginous formation tionship was demonstrated by the matrix that eventually calcifies. At the The first step toward a molecular analysis of Gelatinase B (MMP-9)–defi- same time, the most mature hyper- understanding of the control of endo- cient mice, with which Vu et al. demon- trophic chondrocytes undergo apop- chondral ossification came from a strated that cartilage resorption is tosis, allowing the corresponding area study designed to reveal the function achieved by chondroclasts, multinucle- to be invaded by blood vessels, and of the parathyroid hormone–related ate cells related to osteoclasts, and that both multinucleate, matrix-resorbing peptide (PTHrP) in vivo. Karaplis et al. degradation of the cartilaginous matrix cells and differentiated osteoblasts generated PTHrP-deficient mice and regulates vascular invasion via the appear. The cartilaginous matrix is observed that they exhibit a general- release of an angiogenic factor (9). Two then degraded and replaced by a bone ized abnormality of all skeletal ele- complementary studies later estab- matrix secreted by osteoblasts. ments formed through endochondral lished that this factor is VEGF, that Once this process is completed, the ossification. Underlying this defect VEGF is secreted by hypertrophic chon- only cartilaginous structures remaining are a decrease in chondrocyte prolifer- drocytes, and that it acts as a major are the growth plate cartilages at the ation and an increase in the rate of inducer of vascular invasion (10, 11). two distal ends of the bone. There, chondrocyte hypertrophy in the skele- Because the chondrocyte-specific inac- chondrocytes at each stage of differen- tal condensations (4). Subsequently, tivation of VEGF-A allows for some tiation — resting, proliferating, and two other landmark studies estab- residual vascularization (11), it appears hypertrophic chondrocytes — are lished that the balance between chon- that another VEGF-like factor or a cell arrayed in a linear succession from the drocyte proliferation and chondrocyte type distinct from chondrocytes must most distal to the most medial regions. hypertrophy is controlled by a nega- contribute to the control of vascular This growth plate cartilage therefore tive feedback loop involving two invasion during skeletogenesis. offers a powerful model for studying growth factors, PTHrP and Indian Another major step in our under- cell differentiation in situ. hedgehog (Ihh) (5, 6). They showed standing of the genetic control of endo- Two mechanisms have been generally that PTHrP, secreted by the chondro- chondral bone formation is seen in the proposed to explain how chondrocytes cytes of the perichondrium, signals to analyses of the Ihh-deficient phenotype and osteoblasts could emerge succes- the PTH/PTHrP receptor (PPR) by St.-Jacques et al. (12) and Chung et sively from the same mesenchymal con- expressed on prehypertrophic chon- al. (3). The former group identified densation. First, two populations of drocytes to suppress their differentia- defects affecting both the cartilage for- progenitors might coexist within the tion into hypertrophic chondrocytes. mation and osteoblast differentiation condensations and differentiate along Conversely, prehypertrophic chondro- and demonstrated that Ihh is not only separate lineages into chondrocytes and cytes secrete Ihh, which signals to the required for chondrocyte hypertrophy, osteoblasts. Alternatively, the same cells cells of perichondrium and upregu- but also for expression of Cbfa1, a tran- could differentiate along a single line- lates their synthesis of PTHrP, thereby scription factor required for osteoblast age, first generating chondrocytes, and indirectly slowing the pace of chon- differentiation. In mutant animals, The Journal of Clinical Investigation | February 2001 | Volume 107 | Number 4 405 Figure 1 Molecular control of endochondral ossification. Transcription factors (Cbfa1 and others) promote the differentiation of the type II collagen–producing cells present in the skeletal mesenchymal condensations into Ihh-secreting hypertrophic chondrocytes. Ihh then acts both on the cells of the perichondrium and on the cells of the bone collar. In the perichondrium, Ihh favors the production of PTHrP, which in turn inhibits chondrocyte hypertrophy. In the bone collar, Ihh induces the expression of Cbfa1, which triggers the osteoblastic differentiation of these cells. Hypertrophic chondrocytes also secrete VEGF, which promotes vascular invasion of the skeletal structure. Blood vessels reach the hypertrophic area, chondro- clast/osteoclasts and resorb the ossified cartilaginous matrix. Osteoblasts derived from the bone collar replace this matrix with a bone matrix rich in type I collagen. Cbfa1 is not induced as usual in the ing Ihh expression (16). This function standing of endochondral bone for- cells near the hypertrophic area that of Cbfa1 is independent of its mation has been transformed. Not line the periphery of condensation. osteoblast differentiation function, fur- only is the cascade of events now This area corresponds to the histologi- ther arguing against a transdifferentia- established experimentally, but key cally well defined structure termed the tion of chondrocytes into osteoblasts. regulators have been identified that “bone collar,” the site where calcified As this process is defective in only a few control each step. Still lacking are bone matrix is first observed (13). As a skeletal elements of the Cbfa1-deficient molecular links between these differ- result of the Ihh defect, mice lack mice, there must be other transcription ent factors. For instance, it is osteoblasts in their long bones, demon- factors that carry out this function

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