Fratzl-Zelman Nadja, Blouin Stéphane, Kornak Uwe, Hartmann Markus A, Kurth Andreas A, Zwerina Jochen
Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Center Meidling, 1st Medical Department Hanusch Hospital, 1140 Vienna, Austria.
Vienna Bone and Growth Center, Vienna, Austria.
JBMR Plus. 2025 Jan 23;9(4):ziaf015. doi: 10.1093/jbmrpl/ziaf015. eCollection 2025 Apr.
Pycnodysostosis is a very rare skeletal dysplasia caused by biallelic loss-of-function mutations in cathepsin K, a proteolytic enzyme highly expressed by osteoclasts. Deficiency of cathepsin K impairs bone resorption and further bone remodeling leading to progressive osteosclerosis and bone fragility. Moreover, cathepsin K is also expressed by mature osteocytes. Whether the density, size, and viability of osteocytes and the osteocyte lacuno-canalicular network (OLCN) are also altered, thereby impacting bone quality in pycnodysostosis, has not been explored. We used light microscopy, quantitative backscattered electron imaging, and confocal laser scanning microscopy to examine bone material obtained from a 57-yr-old female patient during surgical correction after femoral head fracture. The cortex consisted of a compact shell of multilayered collagen fibrils oriented in parallel to the periosteum, reflecting vigorous primary bone apposition, multiple osteons with concentrically ordered lamellae, and scattered patches of woven bone. The trabecular area was very dense with trabecular bone volume, varying locally from 30.3% to 67.4%. The bone matrix was overmineralized (average calcium content: +7.5% versus reference values, with a 5-fold increase of highly mineralized areas >27 weight % calcium). Numerous multinucleated osteoclasts and fringes of demineralized matrix were viewed on bone surfaces. The density (number/mm: 193 to 223) and area (20 μm) of the osteocyte lacunae and their canalicular length (0.05 μm/μm bone volume) were within normal range. However, numerous bone packets exhibited (hyper)mineralized osteocyte lacunas (micropetrosis) resulting in a locally disrupted OLCN. In summary, our data indicate that in pycnodysostosis not only osteoclast function is impaired but also osteocyte viability is decreased, leading to micropetrosis, distorted OLCN, and heterogenous mineralization pattern. Thus, osteoclasts and osteocytes both contribute to reduce bone quality. However, the presence of a dense osteocyte network in large areas of the sample indicates that cathepsin K is not essential for the formation of the OLCN.
致密性成骨不全症是一种非常罕见的骨骼发育不良疾病，由组织蛋白酶K的双等位基因功能丧失突变引起，组织蛋白酶K是一种由破骨细胞高度表达的蛋白水解酶。组织蛋白酶K的缺乏会损害骨吸收和进一步的骨重塑，导致进行性骨硬化和骨脆性增加。此外，成熟的骨细胞也表达组织蛋白酶K。骨细胞的密度、大小和活力以及骨细胞陷窝-小管网络（OLCN）是否也发生改变，从而影响致密性成骨不全症的骨质量，尚未得到研究。我们使用光学显微镜、定量背散射电子成像和共聚焦激光扫描显微镜，检查了一名57岁女性患者在股骨头骨折手术矫正期间获得的骨材料。皮质由一层紧密的多层胶原纤维壳组成，这些纤维与骨膜平行排列，反映出旺盛的初级骨附着、多个具有同心排列板层的骨单位以及散在的编织骨斑。小梁区域的小梁骨体积非常密集，局部变化范围为30.3%至67.4%。骨基质矿化过度（平均钙含量：比参考值高7.5%，高矿化区域>27重量%钙增加了5倍）。在骨表面观察到大量多核破骨细胞和脱矿基质边缘。骨细胞陷窝的密度（数量/mm：193至223）和面积（20μm）及其小管长度（0.05μm/μm骨体积）在正常范围内。然而，许多骨包块表现出（过度）矿化的骨细胞陷窝（微石化），导致局部OLCN破坏。总之，我们的数据表明，在致密性成骨不全症中，不仅破骨细胞功能受损，骨细胞活力也降低，导致微石化、OLCN扭曲和矿化模式异质性。因此，破骨细胞和骨细胞都导致骨质量下降。然而，样本大面积区域中密集的骨细胞网络的存在表明，组织蛋白酶K对于OLCN的形成并非必不可少。
