According to current dogma, chondrocytes and osteoblasts are considered independent lineages derived from a common osteochondroprogenitor. In endochondral bone formation, chondrocytes undergo a series of differentiation steps to form the growth plate, and it generally is accepted that death is the ultimate fate of terminally differentiated hypertrophic chondrocytes (HCs). Osteoblasts, accompanying vascular invasion, lay down endochondral bone to replace cartilage. However, whether an HC can become an osteoblast and contribute to the full osteogenic lineage has been the subject of a century-long debate. Here we use a cell-specific tamoxifen-inducible genetic recombination approach to track the fate of murine HCs and show that they can survive the cartilageto-bone transition and become osteogenic cells in fetal and postnatal endochondral bones and persist into adulthood. This discovery of a chondrocyte-to-osteoblast lineage continuum revises concepts of the ontogeny of osteoblasts, with implications for the control of bone homeostasis and the interpretation of the underlying pathological bases of bone disorders.osteoblast ontogeny | chondrocyte lineage | bone repair I n vertebrates, the endochondral bones of the axial and appendicular skeleton (1) develop from mesenchymal progenitors that form condensations in the approximate shape of the future skeletal elements. These progenitors differentiate into chondrocytes, which proliferate, mature, and undergo hypertrophy, forming an avascular cartilaginous template surrounded by a perichondrium. The first osteoblasts differentiate from mesenchymal precursors in the perichondrium and produce a bone collar, which will become the future cortical bone (1). Blood vessels then invade through the bone collar into the hypertrophic cartilage, bringing in osteoblast progenitors from the perichondrium (2), which lay down bone matrix to form the primary ossification center (POC); the cartilage matrix is degraded; and the proximal and distal growth plates, comprising layers of differentiating chondrocytes and spongy/trabecular bone (the primary spongiosa), form (2). Thereafter, linear bone growth continues by endochondral ossification mediated by the growth plate, whereas osteoblasts in the perichondrium form cortical bone on the outer circumference.Chondrocytes and osteoblasts are regarded as separate lineages in development, being derived from common mesenchymal progenitors that express the transcription factors sex determining region Y (SRY)-box 9 (Sox9) and runt related transcription factor 2 (Runx2) (1). Lineage determination toward the chondrocyte or osteoblast fate is controlled by the relative expression of Sox9 and Runx2 (3-5) (Fig. 1A). Sox9 controls chondrocyte proliferation and their progression into hypertrophy (6). Collagen X is the most specific marker of hypertrophic chondrocytes (HCs), the Col10a1 gene being expressed only in prehypertrophic and hypertrophic chondrocytes in the growth plate (7). By contrast, Runx2 is essential for specifying the osteoblast lineage an...

In protein folding and secretion disorders, activation of endoplasmic reticulum (ER) stress signaling (ERSS) protects cells, alleviating stress that would otherwise trigger apoptosis. Whether the stress-surviving cells resume normal function is not known. We studied the in vivo impact of ER stress in terminally differentiating hypertrophic chondrocytes (HCs) during endochondral bone formation. In transgenic mice expressing mutant collagen X as a consequence of a 13-base pair deletion in Col10a1 (13del), misfolded α1(X) chains accumulate in HCs and elicit ERSS. Histological and gene expression analyses showed that these chondrocytes survived ER stress, but terminal differentiation is interrupted, and endochondral bone formation is delayed, producing a chondrodysplasia phenotype. This altered differentiation involves cell-cycle re-entry, the re-expression of genes characteristic of a prehypertrophic-like state, and is cell-autonomous. Concomitantly, expression of Col10a1 and 13del mRNAs are reduced, and ER stress is alleviated. ERSS, abnormal chondrocyte differentiation, and altered growth plate architecture also occur in mice expressing mutant collagen II and aggrecan. Alteration of the differentiation program in chondrocytes expressing unfolded or misfolded proteins may be part of an adaptive response that facilitates survival and recovery from the ensuing ER stress. However, the altered differentiation disrupts the highly coordinated events of endochondral ossification culminating in chondrodysplasia.

Dielectric relaxation and dynamic light scattering of small molecule glass-forming liquids invariably show that the fractional exponent beta(alpha) of the Kohlrausch-Williams-Watts correlation function, exp[-(t/tau(alpha))(beta(alpha))], used to fit the alpha-relaxation data is temperature dependent, increasing towards the value of unity as temperature is raised and the relaxation time tau decreased. Comparing different glass formers, another property is the existence of a correlation between the value of (1-beta(alpha)) at the glass temperature, T(g), and the T(g)-scaled temperature dependence of tau(alpha). We analyze a system of interacting arrays of globally coupled nonlinear oscillators. Each array has its oscillators coupled among themselves with a coupling strength K. The coupling between arrays is characterized by the interarray coupling strength K'. The decay of the phase coherence r for each array is slowed down by the interarray coupling and its time dependence is well approximated at sufficiently long times by exp[-(t/tau)(beta)]. For a fixed K', on increasing K the results exhibit a decrease of tau and a concomitant increase of beta, similar to the properties of dielectric relaxation and dynamic light scattering of glass-forming liquids on increasing temperature. For each K' we define K(g) to be the value of K at which tau is equal to an arbitrarily chosen long time. We find that beta(K(g)) is correlated with the K(g)-scaled K dependence of tau. The results obtained in this manner at various fixed values of K' reproduce the relaxation properties and temperature dependencies of strong, intermediate, and fragile glass-forming liquids.

We analyze a system of interacting arrays of globally coupled nonlinear oscillators. The relaxation in the interacting arrays with different interaction strengths is compared to that in an array not subject to interaction with others. The relaxation of the latter is found to be an exponential function of time. On the other hand the relaxation of the interacting arrays is slowed down and departs from an exponential of time. There exists a crossover time, t c , before which relaxation of the interacting arrays is still an exponential function. However, beyond t c relaxation is no longer exponential but well approximated by a stretched exponential exp͓Ϫ(t/) ␤ ]. The fractional exponent ␤ decreases further from unity with increasing interaction strength. The result bears strong similarity to the basic features suggested by the coupling model and seen experimentally by neutron scattering for relaxation in densely packed interacting molecules in glass-forming liquids.