Endochondral ossification

Endochondral ossification is the process by which the embryonic cartilaginous model of most bones contributes to longitudinal growth and is gradually replaced by bone. During endochondral ossification, chondrocytes proliferate, undergo hypertrophy and die; the cartilage extracellular matrix they construct is then invaded by blood vessels, osteoclasts, bone marrow cells and osteoblasts, the last of which deposit bone on remnants of cartilage matrix. The sequential changes in chondrocyte behaviour are tightly regulated by both systemic factors and locally secreted factors, which act on receptors to effect intracellular signalling and activation of chondrocyte-selective transcription factors. Systemic factors that regulate the behaviour of chondrocytes in growth cartilage include growth hormone and thyroid hormone, and the local secreted factors include Indian hedgehog, parathyroid hormone-related peptide, fibroblast growth factors and components of the cartilage extracellular matrix. Transcription factors that play critical roles in regulation of chondrocyte gene expression under the control of these extracellular factors include Runx2, Sox9 and MEF2C. The invasion of cartilage matrix by the ossification front is dependent on its resorption by members of the matrix metalloproteinase family, as well as the presence of blood vessels and bone-resorbing osteoclast (Mackie et al.) Thyroid hormone and especially triiodothyronine induce morphological hypertrophy of chondrocytes, through binding to thyroid hormone receptors. Further, triiodothyronine increases the total collagen production in chondrocytes, as also terminal differentiation, but triiodothyronine also induces cell death through non-apoptotic modes of physiological death. Triiodothyronine acts by altering intracellular gene expression after receptor binding, and is crucial for growth, as receptor deficiencies lead to dwarfism and growth retardation. Thyroid hormone inhibits the PTHR1 gene, which encodes for a g-protein coupled receptor for parathyroid hormone (PTH) and PTH-like hormones. PTH receptors activate adenylyl cyclase and a phosphatidylinositol-calcium second messenger system. They control the levels of calcium in the blood and thus, ossification as they inhibit hypertrophy upon activation (Mackie, Randau, https://rarediseases.org/rare-diseases/jansen-type-metaphyseal-chondrodysplasia/ ). Oxygen acts upon RUNX2 and HDAC4 in the ossification process. HDAC4 is a class II histone deacetylase/acuc/apha family gene, and if tethered to a promoter, it represses transcription (https://www.ncbi.nlm.nih.gov/gene/9759). Via this mechanism, HDAC4 represses RUNX2 in the ossification process. RUNX2 is a member of the RUNX family of transcription factors, encoding a nuclear protein with an RUND DNA-binding domain. It induces osteoblastic differentiation and skeletal morphogenesis, as it acts upon the DNA and regulatory factors (https://www.ncbi.nlm.nih.gov/gene/860). Thus, RUNX2 acts directly upon chondrocytical hypertrophy. Cyclic adenosine monophosphate (cAMP) act upon protein kinase A (PKA), which phosphorylates proteins if activated. In this case it leads to the inhibition of Sox9 (https://www.nature.com/articles/nm.3314). Sox9 induces cell proliferation and inhibits hypertrophy and is regulating the transcription of the anti-müllerian hormone. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP474 CPTAC Assay Portal]

软骨内成骨是一种生理过程，其中大多数骨骼的胚胎软骨模型参与纵向生长，并逐渐被骨组织取代。在软骨内成骨过程中，软骨细胞进行增殖、肥大并最终死亡；它们所构建的软骨细胞外基质随后被血管、破骨细胞、骨髓细胞和成骨细胞侵袭，其中成骨细胞将骨沉积在软骨基质残留物上。软骨细胞的连续行为变化受到全身因素和局部分泌因素的严格调控，这些因素作用于受体，以影响细胞内信号传导和软骨细胞选择性转录因子的激活。调控生长软骨中软骨细胞行为的全身因素包括生长激素和甲状腺激素，而局部分泌因素包括印度刺猬因子、甲状旁腺激素相关肽、成纤维细胞生长因子和软骨细胞外基质成分。Runx2、Sox9和MEF2C等转录因子在调节软骨细胞基因表达中发挥关键作用，这些表达受细胞外因素的影响。成骨前沿对软骨基质的侵袭依赖于基质金属蛋白酶家族成员的溶解作用，以及血管的存在和骨吸收破骨细胞（Mackie等）。甲状腺激素，尤其是三碘甲状腺原氨酸，通过结合甲状腺激素受体诱导软骨细胞的形态学肥大。此外，三碘甲状腺原氨酸通过非凋亡的生理性死亡方式诱导细胞死亡。三碘甲状腺原氨酸通过与受体结合后改变细胞内基因表达而发挥作用，对生长至关重要，因为受体缺乏会导致侏儒症和生长迟缓。甲状腺激素抑制PTHR1基因，该基因编码甲状旁腺激素（PTH）和类似激素的g蛋白偶联受体。PTH受体激活腺苷酸环化酶和磷脂酰肌醇钙第二信使系统，它们控制血液中的钙水平，从而通过抑制激活后的肥大来调控成骨。氧气作用于成骨过程中的RUNX2和HDAC4。HDAC4是一种II类组蛋白脱乙酰化酶/醋酸/α家族基因，如果与启动子结合，则抑制转录。通过这种机制，HDAC4在成骨过程中抑制RUNX2。RUNX2是RUNX转录因子家族的成员，编码具有RUND DNA结合域的核蛋白。它通过作用于DNA和调节因子诱导成骨细胞分化和骨骼形态发生。因此，RUNX2直接作用于软骨细胞的肥大。环状腺苷单磷酸（cAMP）作用于蛋白激酶A（PKA），如果被激活，则磷酸化蛋白质。在这种情况下，它导致Sox9的抑制。Sox9诱导细胞增殖，抑制肥大，并调节抗缪勒管激素的转录。该途径上的蛋白质具有通过[https://assays.cancer.gov/available_assays?wp_id=WP474 CPTAC检测门户]提供的靶向检测方法。